WO2008061955A1 - Benzoisoindole derivatives and their use as ep4 receptor agonists - Google Patents

Benzoisoindole derivatives and their use as ep4 receptor agonists Download PDF

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Publication number
WO2008061955A1
WO2008061955A1 PCT/EP2007/062497 EP2007062497W WO2008061955A1 WO 2008061955 A1 WO2008061955 A1 WO 2008061955A1 EP 2007062497 W EP2007062497 W EP 2007062497W WO 2008061955 A1 WO2008061955 A1 WO 2008061955A1
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Prior art keywords
dihydro
benzo
isoindol
phenyl
acetic acid
Prior art date
Application number
PCT/EP2007/062497
Other languages
French (fr)
Inventor
Gerard Martin Paul Giblin
Mark Patrick Healy
Helen Susanne Price
Original Assignee
Glaxo Group Limited
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Publication date
Application filed by Glaxo Group Limited filed Critical Glaxo Group Limited
Priority to JP2009537614A priority Critical patent/JP2010510282A/en
Priority to EP07822701A priority patent/EP2081896A1/en
Priority to US12/515,756 priority patent/US20090318523A1/en
Publication of WO2008061955A1 publication Critical patent/WO2008061955A1/en

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    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/58—[b]- or [c]-condensed
    • C07D209/62—Naphtho [c] pyrroles; Hydrogenated naphtho [c] pyrroles
    • C07D209/64—Naphtho [c] pyrroles; Hydrogenated naphtho [c] pyrroles with an oxygen atom in position 1
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Definitions

  • This invention relates to indole derivatives, to processes for their preparation, to pharmaceutical compositions containing them and to their use in medicine.
  • the compounds of the present invention are EP 4 receptor agonists.
  • the EP 4 receptor is a 7-transmembrane receptor and its natural ligand is the prostaglandin PGE 2 .
  • PGE 2 also has affinity for the other EP receptors (types EPi, EP 2 and EP 3 ).
  • the prostanoid EP 4 receptor falls into a group of receptors normally associated with elevation of intracellular cyclic adenosine monophosphate (cAMP) levels.
  • the EP 4 receptor is associated with smooth muscle relaxation, intraocular pressure, pain (in particular inflammatory, neuropathic and visceral pain), inflammation, neuroprotection, lymphocyte differentiation, bone metabolic processes, allergic activities, promotion of sleep, renal regulation, gastric or enteric mucus secretion and duodenal bicarbonate secretion.
  • the EP 4 receptor plays an important role in closure of the ductus arteriosus, vasodepression, inflammation and bone remodeling as reviewed by Narumiya in Prostaglandins & Other Lipid Mediators 2002, 68-69 557-73.
  • indoprofen such as [4-(1-oxo-1 ,3-dihydro-2H-benzo[f]isoindol-2- yl)phenyl]-2-propionic acid, sodium salt have been described by Rufer et. al. in Eur. J. Med. Chem. - Chimica Therapeutica, 1978, 13, 193.
  • the present invention provides a compound selected from the group consisting of:
  • an EP 4 agonist selected from the group consisting of:
  • pharmaceutically acceptable derivative is meant any pharmaceutically acceptable salt, solvate or ester, or salt or solvate of such ester of the compounds of the invention, or any other compound which upon administration to the recipient is capable of providing (directly or indirectly) a compound of the invention or an active metabolite or residue thereof.
  • salts referred to above will be the pharmaceutically acceptable salts, but other salts may find use, for example in the preparation of compounds of the invention and the pharmaceutically acceptable salts thereof.
  • Pharmaceutically acceptable salts include those described by Berge, Bighley and Monkhouse, J. Pharm. Sci., 1977, 66, 1-19.-
  • pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable bases including inorganic bases and organic bases.
  • Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like.
  • Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary, and tertiary amines; substituted amines including naturally occurring substituted amines; and cyclic amines.
  • Particular pharmaceutically acceptable organic bases include arginine, betaine, caffeine, choline, N.N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidrne, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, procaine, purines, theobromine, triethylamine, trimethylamine, tripropyl amine, tris(hydroxymethyl)aminomethane, and the like. Salts may also be formed from basic ion exchange resins, for example polyamine resins.
  • the compounds of the invention may be produced in vivo by metabolism of a suitable prodrug.
  • suitable prodrug may be for example physiologically acceptable metabolically labile esters of the compounds of the invention. These may be formed by esterification of the carboxylic acid group in the parent compound of the invention with, where appropriate, prior protection of any other reactive groups present in the molecule followed by deprotection if required.
  • metabolically labile esters include alkyl esters e.g. methyl ethyl or t-butyl esters esters, C 3 - 6 alkenyl esters e.g. allyl substituted or unsubstituted aminoalkyl esters (e.g.
  • pivaloyloxymethyl 1-pivaloyloxyethyl, acetoxy methyl, 1- acetoxyethyl,1-(1-methoxy-1-methyl)ethylcarbonyloxyethyl, 1-benzoyloxyethyl, isopropoxycarbonyloxymethyl, 1-isopropoxycarbonyloxyethyl, cyclohexylcarbonyloxymethyl, 1-cyclohexylcarbonyloxyethyl ester, cyclohexyloxycarbonyloxymethyl, 1-cyclohexyloxycarbonyloxyethyl, 1-(4- tetrahydropyranyloxy)carbonyloxyethyl or 1-(4- tetrahydropyranyl)carbonyloxyethyl.
  • the present invention encompasses all isomers of the compounds of the invention and their pharmaceutically acceptable derivatives, including all geometric, tautomeric and optical forms, and mixtures thereof (e.g. racemic mixtures).
  • the compounds of the invention are intended for use in pharmaceutical compositions, it will be understood that they are each provided in substantially pure form, for example at least 50% pure, more suitably at least 75% pure and preferably at least 95% pure (% are on a wt/wt basis). Impure preparations of the compounds of the invention may be used for preparing the more pure forms used in the pharmaceutical compositions. Although the purity of intermediate compounds of the present invention is less critical, it will be readily understood that the substantially pure form is preferred as for the compounds of the invention. Preferably, whenever possible, the compounds of the present invention are obtained in crystalline form.
  • solvent of crystallisation may be present in the crystalline product.
  • This invention includes within its scope such solvates.
  • some of the compounds of this invention may be crystallised or recrystallised from solvents containing water. In such cases water of hydration may be formed.
  • This invention includes within its scope stoichiometric hydrates as well as compounds containing variable amounts of water that may be produced by processes such as lyophilisation.
  • different crystallisation conditions may lead to the formation of different polymorphic forms of crystalline products.
  • This invention includes within its scope all polymorphic forms of the compounds of the invention.
  • the present invention also includes within its scope all isotopically-labelled compounds of the invention. Such compounds are identical to those recited in the list of the compounds of the invention except that one or more atoms therein are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds of the invention and pharmaceutically acceptable derivatives thereof include isotopes of hydrogen, carbon, nitrogen, oxygen and fluorine, such as 2H, 3H, 11C, 13C, 14C, 15N, 170, 180 and 18F.
  • Isotopically-labelled compounds of the invention for example those into which radioactive isotopes such as 3H, 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3H, and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. 11C and 18F isotopes are particularly useful in PET (positron emission tomography) and are useful in brain imaging.
  • lsotopically labelled compounds of the invention may be prepared by carrying out the synthetic procedures disclosed in the Schemes and/or in the Examples below, by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent.
  • the compounds of the invention are EP 4 receptor agonists and may therefore be useful in treating EP 4 receptor mediated diseases.
  • the compounds of the invention may be useful in the treatment of pain, for example, chronic articular pain (e.g. rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, gouty arthritis and juvenile arthritis) including the property of disease modification and joint structure preservation; musculoskeletal pain; lower back and neck pain; sprains and strains; neuropathic pain; sympathetically maintained pain; myositis; pain associated with cancer and fibromyalgia; pain associated with migraine; pain associated with influenza or other viral infections, such as the common cold; rheumatic fever; pain associated with functional bowel disorders such as non-ulcer dyspepsia, non-cardiac chest pain and irritable bowel syndrome; pain associated with myocardial ischemia; post operative pain; headache; toothache; and dysmenorrhea.
  • chronic articular pain e.g. rheumatoid arthritis, osteoarthritis, rheumatoid
  • the compounds of the invention may be particularly useful in the treatment of neuropathic pain and symptoms associated therewith.
  • Neuropathic pain syndromes include: diabetic neuropathy;, sciatica; non-specific lower back pain; multiple sclerosis pain; fibromyalgia; HIV-related neuropathy; post-herpetic neuralgia; trigeminal neuralgia; and pain resulting from physical trauma, amputation, cancer, toxins or chronic inflammatory conditions.
  • Symptoms of neuropathic pain include spontaneous shooting and lancinating pain, or ongoing, burning pain.
  • pain associated with normally non- painful sensations such as "pins and needles” (paraesthesias and dysesthesias), increased sensitivity to touch (hyperesthesia), painful sensation following innocuous stimulation (dynamic, static or thermal allodynia), increased sensitivity to noxious stimuli (thermal, cold, mechanical hyperalgesia), continuing pain sensation after removal of the stimulation (hyperpathia) or an absence of or deficit in selective sensory pathways (hypoalgesia).
  • normally non- painful sensations such as "pins and needles” (paraesthesias and dysesthesias), increased sensitivity to touch (hyperesthesia), painful sensation following innocuous stimulation (dynamic, static or thermal allodynia), increased sensitivity to noxious stimuli (thermal, cold, mechanical hyperalgesia), continuing pain sensation after removal of the stimulation (hyperpathia) or an absence of or deficit in selective sensory pathways (hypoalgesia).
  • the compounds of the invention may also be useful in the treatment of inflammation, for example in the treatment of skin conditions (e.g. sunburn, burns, eczema, dermatitis, psoriasis); ophthalmic diseases such as glaucoma, retinitis, retinopathies, uveitis and of acute injury to the eye tissue (e.g. conjunctivitis); lung disorders (e.g. asthma, bronchitis, emphysema, allergic rhinitis, respiratory distress syndrome, pigeon fancier's disease, farmer's lung, COPD); gastrointestinal tract disorders (e.g.
  • an inflammatory component such as vascular disease, migraine, periarteritis nod
  • the compounds of the invention may also be useful in the treatment of immunological diseases such as autoimmune diseases, immunological deficiency diseases or organ transplantation.
  • immunological diseases such as autoimmune diseases, immunological deficiency diseases or organ transplantation.
  • the compounds of the invention may also be effective in increasing the latency of HIV infection.
  • the compounds of the invention may also be useful in the treatment of diseases of excessive or unwanted platelet activation such as intermittent claudication, unstable angina, stroke, and acute coronary syndrome (e.g. occlusive vascular diseases).
  • the compounds of the invention may also be useful as a drug with diuretic action, or may be useful to treat overactive bladder syndrome.
  • the compounds of the invention may also be useful in the treatment of impotence or erectile dysfunction.
  • the compounds of the invention may also be useful in the treatment of bone disease characterised by abnormal bone metabolism or resorption such as osteoporosis (especially postmenopausal osteoporosis), hyper-calcemia, hyperparathyroidism, Paget's bone diseases, osteolysis, hypercalcemia of malignancy with or without bone metastases, rheumatoid arthritis, periodontitis, osteoarthritis, ostealgia, osteopenia, calculosis, lithiasis (especially urolithiasis), gout and ankylosing spondylitis, tendinitis and bursitis.
  • osteoporosis especially postmenopausal osteoporosis
  • hyper-calcemia hyperparathyroidism
  • Paget's bone diseases osteolysis
  • hypercalcemia of malignancy with or without bone metastases rheumatoid arthritis
  • periodontitis osteoarthritis
  • osteoarthritis ostealgia
  • osteopenia
  • the compounds of the invention may also be useful in bone remodelling and/or promoting bone generation and/or promoting fracture healing.
  • the compounds of the invention may also be useful for attenuating the hemodynamic side effects of NSAIDs and COX-2 inhibitors.
  • the compounds of the invention may also be useful in the treatment of cardiovascular diseases such as hypertension or myocardial ischemia; functional or organic venous insufficiency; varicose therapy; haemorrhoids; and shock states associated with a marked drop in arterial pressure (e.g. septic shock).
  • cardiovascular diseases such as hypertension or myocardial ischemia; functional or organic venous insufficiency; varicose therapy; haemorrhoids; and shock states associated with a marked drop in arterial pressure (e.g. septic shock).
  • the compounds of the invention may also be useful in the treatment of neurodegenerative diseases and neurodegeneration such as dementia, particularly degenerative dementia (including senile dementia, Alzheimer's disease, Pick's disease, Huntingdon's chorea, Parkinson's disease and Creutzfeldt-Jakob disease, ALS, motor neuron disease); vascular dementia (including multi-infarct dementia); as well as dementia associated with intracranial space occupying lesions; trauma; infections and related conditions (including HIV infection); metabolism; toxins; anoxia and vitamin deficiency; and mild cognitive impairment associated with ageing, particularly Age Associated Memory Impairment.
  • dementia particularly degenerative dementia (including senile dementia, Alzheimer's disease, Pick's disease, Huntingdon's chorea, Parkinson's disease and Creutzfeldt-Jakob disease, ALS, motor neuron disease); vascular dementia (including multi-infarct dementia); as well as dementia associated with intracranial space occupying lesions; trauma; infections and related conditions (including HIV infection); metabolism; toxins;
  • the compounds of the invention may also be useful in the treatment of neurological disorders and may be useful as neuroprotecting agents.
  • the compounds of the invention may also be useful in the treatment of neurodegeneration following stroke, cardiac arrest, pulmonary bypass, traumatic brain injury, spinal cord injury or the like.
  • the compounds of the invention may also be useful in the treatment of complications of Type 1 diabetes (e.g. diabetic microangiopathy, diabetic retinopathy, diabetic nephropathy, macular degeneration, glaucoma), nephrotic syndrome, aplastic anaemia, uveitis, Kawasaki disease and sarcoidosis.
  • Type 1 diabetes e.g. diabetic microangiopathy, diabetic retinopathy, diabetic nephropathy, macular degeneration, glaucoma
  • nephrotic syndrome e.g. diabetic microangiopathy, diabetic retinopathy, diabetic nephropathy, macular degeneration, glaucoma
  • nephrotic syndrome e.g. diabetic microangiopathy, diabetic retinopathy, diabetic nephropathy, macular degeneration, glaucoma
  • nephrotic syndrome e.g. diabetic microangiopathy, diabetic retinopathy, diabetic nephropathy
  • the compounds of the invention may also be useful in the treatment of kidney dysfunction (nephritis, particularly mesangial proliferative glomerulonephritis, nephritic syndrome), liver dysfunction (hepatitis, cirrhosis) and gastrointestinal dysfunction (diarrhoea).
  • kidney dysfunction nephritis, particularly mesangial proliferative glomerulonephritis, nephritic syndrome
  • liver dysfunction hepatitis, cirrhosis
  • gastrointestinal dysfunction diarrhoea
  • a compound of the invention or a pharmaceutically acceptable derivative thereof for use in human or veterinary medicine there is provided a compound of the invention or a pharmaceutically acceptable derivative thereof for use in the treatment of a condition which is mediated by the action, or loss of action, of PGE 2 at EP 4 receptors.
  • a method of treating a human or animal subject suffering from a condition which is mediated by the action, or by loss of action, of PGE 2 at EP 4 receptors which comprises administering to said subject an effective amount of a compound of the invention or a pharmaceutically acceptable derivative thereof.
  • a method of treating a human or animal subject suffering from a pain, inflammatory, immunological, bone, neurodegenerative or renal disorder comprises administering to said subject an effective amount of a compound of the invention or a pharmaceutically acceptable derivative thereof.
  • a compound of the invention or a pharmaceutically acceptable derivative thereof for the manufacture of a medicament for the treatment of a condition which is mediated by the action of PGE 2 at EP 4 receptors.
  • a compound of the invention or a pharmaceutically acceptable derivative thereof for the manufacture of a medicament for the treatment or prevention of a condition such as a pain, inflammatory, immunological, bone, neurodegenerative or renal disorder.
  • compositions are conveniently administered in the form of pharmaceutical compositions.
  • Such compositions may conveniently be presented for use in conventional manner in admixture with one or more physiologically acceptable carriers or excipients.
  • a pharmaceutical composition comprising a compound of the invention or a pharmaceutically acceptable derivative thereof adapted for use in human or veterinary medicine.
  • the formulations of the present invention comprise the compounds of the invention or a pharmaceutically acceptable derivative thereof together with one or more acceptable carriers or diluents therefor and optionally other therapeutic ingredients.
  • the carrier(s) must be "acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • the formulations include those suitable for oral, parenteral (including subcutaneous e.g. by injection or by depot tablet, intradermal, intrathecal, intramuscular e.g. by depot and intravenous), rectal and topical (including dermal, buccal and sublingual) administration although the most suitable route may depend upon for example the condition and disorder of the recipient.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy, (see for example methods disclosed in 'Remington - The Science and Practice of Pharmacy', 21 st Edition, Lippincott, Williams & Wilkins, USA, 2005 and references therein).
  • All methods include the step of bringing into association the compound of the invention or a pharmaceutically acceptable acid addition salt thereof ("active ingredient") with the carrier which constitutes one or more accessory ingredients.
  • active ingredient a pharmaceutically acceptable acid addition salt thereof
  • the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
  • Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets (e.g.
  • chewable tablets in particular for paediatric administration each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
  • the active ingredient may also be presented as a bolus, electuary or paste.
  • a tablet may be made by compression or moulding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating, surface active or dispersing agent.
  • Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein.
  • Formulations for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of a sterile liquid carrier, for example, water-for-injection, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
  • Formulations for rectal administration may be presented as a suppository with the usual carriers such as cocoa butter, hard fat or polyethylene glycol.
  • Formulations for topical administration in the mouth include lozenges comprising the active ingredient in a flavoured basis such as sucrose and acacia or tragacanth, and pastilles comprising the active ingredient in a basis such as gelatin and glycerin or sucrose and acacia.
  • the compounds of the invention may also be formulated as depot preparations. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds of the invention may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • formulations may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavouring agents.
  • the EP 4 receptor compounds for use in the present invention may be used in combination with other therapeutic agents, for example COX-2 inhibitors, such as celecoxib, rofecoxib, valdecoxib or parecoxib; 5-lipoxygenase inhibitors; analgesics such as paracetamol; NSAID's, such as diclofenac, indomethacin, nabumetone, naproxen or ibuprofen; leukotriene receptor antagonists; DMARD's such as methotrexate; sodium channel blockers, such as lamotrigine; N-type calcium channel antagonists; NMDA receptor modulators, such as glycine receptor antagonists; gabapentin, pregabalin and related compounds; tricyclic antidepressants such as amitriptyline; neurone stabilising antiepileptic drugs; mono-aminergic uptake inhibitors such as venlafaxine; opioid analgesics; local anaesthetics; 5HTi agonist
  • the invention thus provides, in a further embodiment, a combination comprising a compound of the invention or a pharmaceutically acceptable derivative thereof together with a further therapeutic agent or agents.
  • a combination comprising a compound of the invention or a pharmaceutically acceptable derivative thereof and paracetamol.
  • compositions comprising a compound of the invention or a pharmaceutically acceptable derivative thereof, paracetamol and a pharmaceutically acceptable carrier or diluent therefor.
  • the individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations.
  • each compound may differ from that when the compound is used alone. Appropriate doses will be readily appreciated by those skilled in the art.
  • a proposed daily dosage of a compound of the invention, or a pharmaceutically acceptable salt thereof, for the treatment of man is from 0.001 to 30 mg/kg body weight per day and more particularly 0.1 to 3 mg/kg body weight per day, calculated as the free acid, which may be administered as a single or divided dose, for example one to four times per day.
  • the dose range for adult human beings is generally from 0.1 to 1000 mg/day, such as from 10 to 800 mg/day, preferably 10 to 200 mg/day, calculated as the free acid.
  • a suitable daily dosage of paracetamol is up to 4000 mg per day.
  • Suitable unit doses include 200, 400, 500 and 1000 mg, one, two, three or four times per day.
  • the precise amount of the compounds of the invention administered to a host, particularly a human patient, will be the responsibility of the attendant physician. However, the dose employed will depend on a number of factors including the age and sex of the patient, the precise condition being treated and its severity, the route of administration, and any possible combination therapy that may be being undertaken.
  • R 1 represents Ci -4 alkyl
  • R represents Ci -4 alkyl or CH 2 Ph
  • R 2 and R 3 independently represent Ci -4 alkyl or CH 2 Ph;
  • R 4 represents Ci -4 alkyl, Ci -4 alkoxy or CF 3 ;
  • R 5 represents C1- 6 alkyl
  • R 6 represents Ci -4 alkyl; m and n independently represent 0 or 1 ; and
  • R * R 3 or R 6 .
  • step ii is carried out as a two step process in which R 2 is added and then R 3 , or vice versa.
  • the term 'C h alky!' includes straight chain and branched chain alkyl groups containing 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, iso- propyl, n-butyl, /so-butyl and tert-butyl.
  • the term 'Ci -6 alkyl' may be interpreted accordingly.
  • methyl dimethylphthalate may be purchased from Sigma-Aldrich Co. Ltd.
  • X represents halo, for example F or Cl.
  • LHMDS Lithium hexamethyldisylazide .
  • Aqueous solvent Water + 0.05% Formic Acid
  • Organic solvent Acetonithle + 0.05% Formic Acid
  • Chromatographic methods include column chromatography, flash chromatography, HPLC (high performance liquid chromatography), SFC
  • Biotage when used herein refers to commercially available prepacked silica gel cartridges.
  • Aqueous solvent Water + 0.1% Formic Acid
  • Runtime 13.5 minutes, comprising 10-minute gradient followed by a 3.5 minute column flush and re-equilibration step.
  • Runtime 13.5 minutes, comprising 6-minute gradient followed by a 7.5 minute column flush and re-equilibration step.
  • Methyl dimethylphthalate(10g, 48mmol) and LHMDS (1 M in hexanes, 196ml, 192mmol) in THF (150ml) were cooled to O 0 C.
  • * 1 ,4-dihydroxy-2,3-naphthalenedicarboxylate may be prepared in accordance with the method disclosed in International Patent Application, Publication Number WO02/064564.
  • Bromoethane (0.359g, 3.29mmol) was added to a stirred solution of diethyl 1 ,4- dihydroxy-2,3-naphthalenedicarboxylate (1g, 3.29mmol) and potassium carbonate (0.454g, 3.29mmol) in acetone (25ml).
  • the reaction mixture was refluxed for 24 hours under an atmosphere of argon.
  • the resulting mixture was evaporated and the residue was partitioned between 2 x ethylacetate and water. The combined organics were washed with water and dried over magnesium sulphate.
  • Benzyl bromide (1.32ml, 11.1mmol) was added to a stirred solution of diethyl 1- (ethyloxy)-4-hydroxy-2,3-naphthalenedicarboxylate (2.45g, 7.38mmol) and potassium carbonate (1.53g, 11.1mmol) in acetone (50ml).
  • the reaction mixture was refluxed for 1 hour under an atmosphere of argon.
  • the resulting mixture was evaporated and the residue was partitioned between 2 x ethylacetate and brine.
  • the combined organics were washed with water and dried over magnesium sulphate.
  • the reaction was basified with 880 ammonia and then evaporated.
  • the mixture was partitioned between x2 dichloromethane and water using a hydrophobic frit.
  • the organic extracts were evaporated down.
  • the isomers were separated using HPLC chromatography.
  • Example 24 was prepared using methanol as a solvent instead of ethanol.
  • HEK-293(T) cells expressing the recombinant human prostanoid EP 4 receptor were grown as a monolayer culture in DMEM-F12/F12 containing glutamax Il (Gibco) and supplemented with 10% foetal bovine serum and 0.4mg.ml-1 G418.
  • HEK-EP 4 cells were pre-treated 24hr and 30mins prior to the experiment with 10 ⁇ M indomethacin and harvested using Versene containing 10 ⁇ M indomethacin.
  • the cells were resuspended in assay buffer (DMEM:F12, 10 ⁇ M indomethacin and 200 ⁇ M IBMX) at 1 x10 6 cells per ml and incubated for 20min at 37°C. Thereafter, 50 ⁇ l of cells were added to 5OuI agonist (compound of Formula (I)) and incubated at 37°C for 4 minutes before stopping reactions with 100 ⁇ l of 1% triton X-100.
  • cAMP levels in the cell lysates were determined using a competition binding assay. In this assay the ability of cell lysates to inhibit 3H-cAMP (Amersham) binding to the binding subunit of protein kinase A was measured and cAMP levels were calculated from a standard curve.
  • the examples of the present invention were tested in the above-mentioned assay and exhibited pEC 50 values of 6.4 or higher and intrinsic activities of 30% or higher.

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Abstract

The present invention relates to benzoisoindole phenylacetic acid derivatives, to processes for their preparation, to pharmaceutical compositions containing them and to their use in medicine as EP4 receptor organists.

Description

BENZOISOINDOLE DERIVATIVES AND THEIR USE AS EP4 RECEPTOR AGONISTS
This invention relates to indole derivatives, to processes for their preparation, to pharmaceutical compositions containing them and to their use in medicine.
The compounds of the present invention are EP4 receptor agonists.
A number of review articles describe the characterization and therapeutic relevance of the prostanoid receptors as well as the most commonly used selective agonists and antagonists: Eicosanoids; From Biotechnology to Therapeutic Applications, Folco, Samuelsson, Maclouf, and VeIo eds, Plenum Press, New York, 1996, chap. 14, 137- 154 and Journal of Lipid Mediators and Cell Signalling, 1996, 14, 83-87 and Prostanoid Receptors, Structure, Properties and Function, S Narumiya et al, Physiological Reviews 1999, 79(4), 1193-126.
The EP4 receptor is a 7-transmembrane receptor and its natural ligand is the prostaglandin PGE2. PGE2 also has affinity for the other EP receptors (types EPi, EP2 and EP3). The prostanoid EP4 receptor falls into a group of receptors normally associated with elevation of intracellular cyclic adenosine monophosphate (cAMP) levels. The EP4 receptor is associated with smooth muscle relaxation, intraocular pressure, pain (in particular inflammatory, neuropathic and visceral pain), inflammation, neuroprotection, lymphocyte differentiation, bone metabolic processes, allergic activities, promotion of sleep, renal regulation, gastric or enteric mucus secretion and duodenal bicarbonate secretion. The EP4 receptor plays an important role in closure of the ductus arteriosus, vasodepression, inflammation and bone remodeling as reviewed by Narumiya in Prostaglandins & Other Lipid Mediators 2002, 68-69 557-73.
A number of publications have demonstrated that PGE2 acting through the EP4 receptor subtype, and EP4 agonists alone, can regulate inflammatory cytokines after an inflammatory stimulus. Takayama et al in the Journal of Biological Chemistry 2002, 277(46), 44147-54 showed PGE2 modulates inflammation during inflammatory diseases by suppressing macrophage derived chemokine production via the EP4 receptor. In Bioorganic & Medicinal Chemistry 2002, 10(7), 2103-2110, Maruyama et al demonstrate the selective EP4 receptor agonist (ONO-AE1-437) suppresses LPS induced TNF-α in human whole blood whilst increasing the levels of IL-10. An article in Anesthesiology, 2002, 97,170-176 suggests that a selective EP4 receptor agonist (ONO-AE1-329) effectively inhibited mechanical and thermal hyperalgesia and inflammatory reactions in acute and chronic monoarthritis.
Two independent articles from Sakuma et al in Journal of Bone and Mineral Research 2000, 15(2), 218-227 and Miyaura et al in Journal of Biological Chemistry 2000, 275(26), 19819-23, report impaired osteoclast formation in cells cultured from EP4 receptor knock-out mice. Yoshida et al in Proceedings of the National Academy of Sciences of the United States of America 2002, 99(7), 4580- 4585, by use of mice lacking each of the PGE2 receptor EP subtypes, identified EP4 as the receptor that mediates bone formation in response to PGE2 administration. They also demonstrated a selective EP4 receptor agonist (ONO-4819) consistently induces bone formation in wild type mice. Additionally, Terai et al in Bone 2005, 37(4), 555-562 have shown the presence of a selective EP4 receptor agonist (ONO- 4819) enhanced the bone-inducing capacity of rhBMP-2, a therapeutic cytokine that can induce bone formation.
Further research by Larsen et al shows the effects of PGE2 on secretion in the second part of the human duodenum is mediated through the EP4 receptor (Acta. Physiol. Scand. 2005, 185, 133-140). Also, it has been shown a selective EP4 receptor agonist (ONO-AE1-329) can protect against colitis in rats (Nitta et al in Scandinavian Journal of Immunology 2002, 56(1), 66-75).
Dore et al in The European Journal of Neuroscience 2005, 22(9), 2199-206 have shown that PGE2 can protect neurons against amyloid beta peptide toxicity by acting on EP2 and EP4 receptors. Furthermore Dore has demonstrated in Brain Research 2005, 1066(1-2), 71-77 that an EP4 receptor agonist (ONO-AE1-329) protects against neurotoxicity in an acute model of excitotoxicity in the brain.
Woodward et al in Journal of Lipid Mediators 1993, 6(1-3), 545-53 found intraocular pressure could be lowered using selective prostanoid agonists. Two papers in Investigative Ophthalmology & Visual Science have shown the prostanoid EP4 receptor is expressed in human lens epithelial cells (Mukhopadhyay et al 1999, 40(1), 105-12), and suggest a physiological role for the prostanoid EP4 receptor in modulation of flow in the trabecular framework of the eye (Hoyng et al 1999, 40(11), 2622-6).
Compounds exhibiting EP4 receptor binding activity have been described in, for example, WO98/55468, WO00/18744, WO00/03980, WO00/15608, WO0016760, WO00/21532, EP0855389, EP0985663, WO02/50031 , WO02/50032, WO 02/50033, WO02/064564, WO 03/103604, WO03/077910, WO03/086371 , WO04/037813, WO04/067524, WO04/085430, US04/142969, WO05/021508, WO05/105733, WO05/105732, WO05/080367, WO05/037812, WO05/116010, and WO 06/122403
Derivatives of indoprofen such as [4-(1-oxo-1 ,3-dihydro-2H-benzo[f]isoindol-2- yl)phenyl]-2-propionic acid, sodium salt have been described by Rufer et. al. in Eur. J. Med. Chem. - Chimica Therapeutica, 1978, 13, 193.
Compounds of the present invention have been shown to have advantageous in vivo and in vitro activities when tested in the biological assays described herein.
The present invention provides a compound selected from the group consisting of:
{4-[1 ,3-Dioxo-4,9-bis(propyloxy)-1 ,3-dihydro-2H-benzo[f]isoindol-2-yl]-3- methylphenyl}acetic acid;
[4-[4,9-Bis(ethyloxy)-1 ,3-dioxo-1 ,3-dihydro-2H-benzo[f]isoindol-2-yl]-3- (methyloxy)phenyl]acetic acid; [4-[4,9-Bis(ethyloxy)-1 ,3-dioxo-1 ,3-dihydro-2H-benzo[f]isoindol-2-yl]-3-
(trifluoromethyl)phenyl]acetic acid;
{4-[4,9-Bis(ethyloxy)-1 ,3-dioxo-1 ,3-dihydro-2H-benzo[f]isoindol-2-yl]-3- methylphenyl}acetic acid; {4-[4,9-Bis(ethyloxy)-6-methyl-1 ,3-dioxo-1 ,3-dihydro-2H-benzo[/]isoindol-2- yl]phenyl}acetic acid;
{3-Methyl-4-[1-oxo-4,9-bis(propyloxy)-1 ,3-dihydro-2H-benzo[f]isoindol-2- yl]phenyl}acetic acid;
(4-{4,9-Bis(1-methylethoxy)-1 -oxo-1 , 3-dihydro-2H-benzo[f]isoindol-2-yl}-3- methylphenyl)acetic acid; μ-K.Θ-BisCethyloxyH-oxo-I .S-dihydro^H-benzofflisoindol^-ylJ-S-
(trifluoromethyl)phenyl]acetic acid;
(4-{4-(Ethyloxy)-1 ,3-dioxo-9-[(phenylmethyl)oxy]-1 ,3-dihydro-2H-benzo[f]isoindol-
2-yl}phenyl)acetic acid; (4-{4-[1-Methylethoxy]-9-[(2-methylpropyl)oxy]-1 ,3-dioxo-1 ,3-dihydro-2H- benzo[f]isoindol-2-yl}phenyl)acetic acid;
(4-{4-[1-Methylethoxy]-9-[(1-methylpropyl)oxy]-1 ,3-dioxo-1 ,3-dihydro-2H- benzo[f]isoindol-2-yl}phenyl)acetic acid;
(4-{4-(Ethyloxy)-9-[(1-methylpropyl)oxy]-1 ,3-dioxo-1 ,3-dihydro-2H- benzo[f]isoindol-2-yl}phenyl)acetic acid;
(4-{4-(Ethyloxy)-9-[(2-methylpropyl)oxy]-1 ,3-dioxo-1 ,3-dihydro-2H- benzo[f]isoindol-2-yl}phenyl)acetic acid;
{4-[4-(Butyloxy)-9-(ethyloxy)-1 ,3-dioxo-1 ,3-dihydro-2H-benzo[f]isoindol-2- yl]phenyl}acetic acid; (4-{4-(Methyloxy)-9-[(1 -methylpropyl)oxy]-1 ,3-dioxo-1 ,3-dihydro-2H- benzo[f]isoindol-2-yl}phenyl)acetic acid;
{4-[4-(Butyloxy)-9-(ethyloxy)-1-oxo-1 ,3-dihydro-2H-benzo[f]isoindol-2- yl]phenyl}acetic acid;
{4-[9-(Butyloxy)-4-(ethyloxy)-1 -oxo-1 , 3-dihydro-2H-benzo[f]isoindol-2- yl]phenyl}acetic acid;
(4-{4-(Ethyloxy)-9-[(1-methylpropyl)oxy]-1 -oxo-1 , 3-dihydro-2H-benzo[f]isoindol-2- yl}phenyl)acetic acid; (4-{9-(Ethyloxy)-4-[(2-methylpropyl)oxy]-1-oxo-1 ,3-dihydro-2H-benzo[f]isoindol-2- yl}phenyl)acetic acid;
-R-(4-{4-(Methyloxy)-9-[(1 -methylpropyl)oxy]-1 -oxo-1 , 3-dihydro-2H- benzo[f]isoindol-2-yl}phenyl)acetic acid; -S-(4-{4-(Methyloxy)-9-[(1-methylpropyl)oxy]-1-oxo-1 ,3-dihydro-2H- benzo[f]isoindol-2-yl}phenyl)acetic acid;
(4-{4-[1 -Methylethoxy]-9-[(2-methylpropyl)oxy]-1 -oxo-1 , 3-dihydro-2H- benzo[f]isoindol-2-yl}phenyl)acetic acid;
(4-{9-[1-Methylethoxy]-4-[(2-methylpropyl)oxy]-1 -oxo-1 , 3-dihydro-2H- benzo[f]isoindol-2-yl}phenyl)acetic acid;
(4-{9-(Butyloxy)-4-[1-methylethoxy]-1 -oxo-1 , 3-dihydro-2H-benzo[f]isoindol-2- yl}phenyl)acetic acid; and/or a pharmaceutically acceptable derivative thereof (hereafter 'the compounds of the invention').
In a further embodiment of the invention there is provided an EP4 agonist selected from the group consisting of:
{4-[4,9-Bis(ethyloxy)-1 ,3-dioxo-1 ,3-dihydro-2H-benzo[f]isoindol-2-yl]-3- methylphenyljacetic acid;
{4-[4,9-Bis(ethyloxy)-6-methyl-1 ,3-dioxo-1 ,3-dihydro-2H-benzo[f]isoindol-2- yl]phenyl}acetic acid;
{3-Methyl-4-[1-oxo-4,9-bis(propyloxy)-1 ,3-dihydro-2H-benzo[f]isoindol-2- yl]phenyl}acetic acid;
(4-{4,9-Bis(1 -methylethoxy)-1 -oxo-1 ,3-dihydro-2H-benzo[f]isoindol-2-yl}-3- methylphenyl)acetic acid; [4-[4,9-Bis(ethyloxy)-1 -oxo-1 ,3-dihydro-2H-benzo[f]isoindol-2-yl]-3-
(trifluoromethyl)phenyl]acetic acid;
(4-{4-[1 -Methylethoxy]-9-[(1 -methylpropyl)oxy]-1 ,3-dioxo-1 ,3-dihydro-2H- benzo[f]isoindol-2-yl}phenyl)acetic acid;
(4-{4-(Ethyloxy)-9-[(2-methylpropyl)oxy]-1 ,3-dioxo-1 ,3-dihydro-2H- benzo[f]isoindol-2-yl}phenyl)acetic acid;
{4-[4-(Butyloxy)-9-(ethyloxy)-1 ,3-dioxo-1 ,3-dihydro-2H-benzo[f]isoindol-2- yl]phenyl}acetic acid; (4-{4-(Methyloxy)-9-[(1 -methylpropyl)oxy]-1 ,3-dioxo-1 ,3-dihydro-2H- benzo[f]isoindol-2-yl}phenyl)acetic acid;
(4-{4-(Ethyloxy)-9-[(1 -methylpropyl)oxy]-1 -oxo-1 ,3-dihydro-2H-benzo[f]isoindol-2- yl}phenyl)acetic acid; (4-{4-(Methyloxy)-9-[(1-methylpropyl)oxy]-1-oxo-1 ,3-dihydro-2H-benzo[f]isoindol- 2-yl}phenyl)acetic acid; and
(4-{4-(Methyloxy)-9-[(1-methylpropyl)oxy]-1 -oxo-1 , 3-dihydro-2H-benzo[f]isoindol- 2-yl}phenyl)acetic acid; and/or a pharmaceutically acceptable derivative thereof.
By pharmaceutically acceptable derivative is meant any pharmaceutically acceptable salt, solvate or ester, or salt or solvate of such ester of the compounds of the invention, or any other compound which upon administration to the recipient is capable of providing (directly or indirectly) a compound of the invention or an active metabolite or residue thereof.
It will be appreciated that, for pharmaceutical use, the salts referred to above will be the pharmaceutically acceptable salts, but other salts may find use, for example in the preparation of compounds of the invention and the pharmaceutically acceptable salts thereof.
Pharmaceutically acceptable salts include those described by Berge, Bighley and Monkhouse, J. Pharm. Sci., 1977, 66, 1-19.- The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable bases including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary, and tertiary amines; substituted amines including naturally occurring substituted amines; and cyclic amines. Particular pharmaceutically acceptable organic bases include arginine, betaine, caffeine, choline, N.N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidrne, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, procaine, purines, theobromine, triethylamine, trimethylamine, tripropyl amine, tris(hydroxymethyl)aminomethane, and the like. Salts may also be formed from basic ion exchange resins, for example polyamine resins.
It will be appreciated that the compounds of the invention may be produced in vivo by metabolism of a suitable prodrug. Such prodrugs may be for example physiologically acceptable metabolically labile esters of the compounds of the invention. These may be formed by esterification of the carboxylic acid group in the parent compound of the invention with, where appropriate, prior protection of any other reactive groups present in the molecule followed by deprotection if required. Examples of such metabolically labile esters include
Figure imgf000008_0001
alkyl esters e.g. methyl ethyl or t-butyl esters esters, C3-6 alkenyl esters e.g. allyl substituted or unsubstituted aminoalkyl esters (e.g. aminoethyl, 2-(N1N- diethylamino) ethyl, or 2-(4-morpholino)ethyl esters or acyloxyalkyl esters such as, acyloxymethyl or 1 -acyloxyethyl e.g. pivaloyloxymethyl, 1-pivaloyloxyethyl, acetoxy methyl, 1- acetoxyethyl,1-(1-methoxy-1-methyl)ethylcarbonyloxyethyl, 1-benzoyloxyethyl, isopropoxycarbonyloxymethyl, 1-isopropoxycarbonyloxyethyl, cyclohexylcarbonyloxymethyl, 1-cyclohexylcarbonyloxyethyl ester, cyclohexyloxycarbonyloxymethyl, 1-cyclohexyloxycarbonyloxyethyl, 1-(4- tetrahydropyranyloxy)carbonyloxyethyl or 1-(4- tetrahydropyranyl)carbonyloxyethyl.
It is to be understood that the present invention encompasses all isomers of the compounds of the invention and their pharmaceutically acceptable derivatives, including all geometric, tautomeric and optical forms, and mixtures thereof (e.g. racemic mixtures).
Since the compounds of the invention are intended for use in pharmaceutical compositions, it will be understood that they are each provided in substantially pure form, for example at least 50% pure, more suitably at least 75% pure and preferably at least 95% pure (% are on a wt/wt basis). Impure preparations of the compounds of the invention may be used for preparing the more pure forms used in the pharmaceutical compositions. Although the purity of intermediate compounds of the present invention is less critical, it will be readily understood that the substantially pure form is preferred as for the compounds of the invention. Preferably, whenever possible, the compounds of the present invention are obtained in crystalline form.
When some of the compounds of this invention are allowed to crystallise or are recrystallised from organic solvents, solvent of crystallisation may be present in the crystalline product. This invention includes within its scope such solvates. Similarly, some of the compounds of this invention may be crystallised or recrystallised from solvents containing water. In such cases water of hydration may be formed. This invention includes within its scope stoichiometric hydrates as well as compounds containing variable amounts of water that may be produced by processes such as lyophilisation. In addition, different crystallisation conditions may lead to the formation of different polymorphic forms of crystalline products. This invention includes within its scope all polymorphic forms of the compounds of the invention.
The present invention also includes within its scope all isotopically-labelled compounds of the invention. Such compounds are identical to those recited in the list of the compounds of the invention except that one or more atoms therein are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention and pharmaceutically acceptable derivatives thereof include isotopes of hydrogen, carbon, nitrogen, oxygen and fluorine, such as 2H, 3H, 11C, 13C, 14C, 15N, 170, 180 and 18F.
Isotopically-labelled compounds of the invention, for example those into which radioactive isotopes such as 3H, 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3H, and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. 11C and 18F isotopes are particularly useful in PET (positron emission tomography) and are useful in brain imaging. Further substitution with heavier isotopes such as deuterium, i.e., 2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances, lsotopically labelled compounds of the invention may be prepared by carrying out the synthetic procedures disclosed in the Schemes and/or in the Examples below, by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent.
The compounds of the invention are EP4 receptor agonists and may therefore be useful in treating EP4 receptor mediated diseases.
In particular the compounds of the invention may be useful in the treatment of pain, for example, chronic articular pain (e.g. rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, gouty arthritis and juvenile arthritis) including the property of disease modification and joint structure preservation; musculoskeletal pain; lower back and neck pain; sprains and strains; neuropathic pain; sympathetically maintained pain; myositis; pain associated with cancer and fibromyalgia; pain associated with migraine; pain associated with influenza or other viral infections, such as the common cold; rheumatic fever; pain associated with functional bowel disorders such as non-ulcer dyspepsia, non-cardiac chest pain and irritable bowel syndrome; pain associated with myocardial ischemia; post operative pain; headache; toothache; and dysmenorrhea.
The compounds of the invention may be particularly useful in the treatment of neuropathic pain and symptoms associated therewith. Neuropathic pain syndromes include: diabetic neuropathy;, sciatica; non-specific lower back pain; multiple sclerosis pain; fibromyalgia; HIV-related neuropathy; post-herpetic neuralgia; trigeminal neuralgia; and pain resulting from physical trauma, amputation, cancer, toxins or chronic inflammatory conditions. Symptoms of neuropathic pain include spontaneous shooting and lancinating pain, or ongoing, burning pain. In addition, there is included pain associated with normally non- painful sensations such as "pins and needles" (paraesthesias and dysesthesias), increased sensitivity to touch (hyperesthesia), painful sensation following innocuous stimulation (dynamic, static or thermal allodynia), increased sensitivity to noxious stimuli (thermal, cold, mechanical hyperalgesia), continuing pain sensation after removal of the stimulation (hyperpathia) or an absence of or deficit in selective sensory pathways (hypoalgesia).
The compounds of the invention may also be useful in the treatment of inflammation, for example in the treatment of skin conditions (e.g. sunburn, burns, eczema, dermatitis, psoriasis); ophthalmic diseases such as glaucoma, retinitis, retinopathies, uveitis and of acute injury to the eye tissue (e.g. conjunctivitis); lung disorders (e.g. asthma, bronchitis, emphysema, allergic rhinitis, respiratory distress syndrome, pigeon fancier's disease, farmer's lung, COPD); gastrointestinal tract disorders (e.g. aphthous ulcer, Crohn's disease, atopic gastritis, gastritis varialoforme, ulcerative colitis, coeliac disease, regional ileitis, irritable bowel syndrome, inflammatory bowel disease, gastrointestinal reflux disease, diarrhoea, constipation); organ transplantation; other conditions with an inflammatory component such as vascular disease, migraine, periarteritis nodosa, thyroiditis, aplastic anaemia, Hodgkin's disease, sclerodoma, myaesthenia gravis, multiple sclerosis, sorcoidosis, nephrotic syndrome, Bechet's syndrome, polymyositis, gingivitis, myocardial ischemia, pyrexia, systemic lupus erythematosus, polymyositis, tendinitis, bursitis, and Sjogren's syndrome.
The compounds of the invention may also be useful in the treatment of immunological diseases such as autoimmune diseases, immunological deficiency diseases or organ transplantation. The compounds of the invention may also be effective in increasing the latency of HIV infection. The compounds of the invention may also be useful in the treatment of diseases of excessive or unwanted platelet activation such as intermittent claudication, unstable angina, stroke, and acute coronary syndrome (e.g. occlusive vascular diseases).
The compounds of the invention may also be useful as a drug with diuretic action, or may be useful to treat overactive bladder syndrome.
The compounds of the invention may also be useful in the treatment of impotence or erectile dysfunction.
The compounds of the invention may also be useful in the treatment of bone disease characterised by abnormal bone metabolism or resorption such as osteoporosis (especially postmenopausal osteoporosis), hyper-calcemia, hyperparathyroidism, Paget's bone diseases, osteolysis, hypercalcemia of malignancy with or without bone metastases, rheumatoid arthritis, periodontitis, osteoarthritis, ostealgia, osteopenia, calculosis, lithiasis (especially urolithiasis), gout and ankylosing spondylitis, tendinitis and bursitis.
The compounds of the invention may also be useful in bone remodelling and/or promoting bone generation and/or promoting fracture healing.
The compounds of the invention may also be useful for attenuating the hemodynamic side effects of NSAIDs and COX-2 inhibitors.
The compounds of the invention may also be useful in the treatment of cardiovascular diseases such as hypertension or myocardial ischemia; functional or organic venous insufficiency; varicose therapy; haemorrhoids; and shock states associated with a marked drop in arterial pressure (e.g. septic shock).
The compounds of the invention may also be useful in the treatment of neurodegenerative diseases and neurodegeneration such as dementia, particularly degenerative dementia (including senile dementia, Alzheimer's disease, Pick's disease, Huntingdon's chorea, Parkinson's disease and Creutzfeldt-Jakob disease, ALS, motor neuron disease); vascular dementia (including multi-infarct dementia); as well as dementia associated with intracranial space occupying lesions; trauma; infections and related conditions (including HIV infection); metabolism; toxins; anoxia and vitamin deficiency; and mild cognitive impairment associated with ageing, particularly Age Associated Memory Impairment.
The compounds of the invention may also be useful in the treatment of neurological disorders and may be useful as neuroprotecting agents. The compounds of the invention may also be useful in the treatment of neurodegeneration following stroke, cardiac arrest, pulmonary bypass, traumatic brain injury, spinal cord injury or the like.
The compounds of the invention may also be useful in the treatment of complications of Type 1 diabetes (e.g. diabetic microangiopathy, diabetic retinopathy, diabetic nephropathy, macular degeneration, glaucoma), nephrotic syndrome, aplastic anaemia, uveitis, Kawasaki disease and sarcoidosis.
The compounds of the invention may also be useful in the treatment of kidney dysfunction (nephritis, particularly mesangial proliferative glomerulonephritis, nephritic syndrome), liver dysfunction (hepatitis, cirrhosis) and gastrointestinal dysfunction (diarrhoea).
It is to be understood that reference to treatment includes both treatment of established symptoms and prophylactic treatment.
According to a further embodiment of the invention, there is provided a compound of the invention or a pharmaceutically acceptable derivative thereof for use in human or veterinary medicine. According to another embodiment of the invention, there is provided a compound of the invention or a pharmaceutically acceptable derivative thereof for use in the treatment of a condition which is mediated by the action, or loss of action, of PGE2 at EP4 receptors.
According to a further embodiment of the invention, there is provided a method of treating a human or animal subject suffering from a condition which is mediated by the action, or by loss of action, of PGE2 at EP4 receptors which comprises administering to said subject an effective amount of a compound of the invention or a pharmaceutically acceptable derivative thereof.
According to a further embodiment of the invention there is provided a method of treating a human or animal subject suffering from a pain, inflammatory, immunological, bone, neurodegenerative or renal disorder, which method comprises administering to said subject an effective amount of a compound of the invention or a pharmaceutically acceptable derivative thereof.
According to another embodiment of the invention, there is provided the use of a compound of the invention or a pharmaceutically acceptable derivative thereof for the manufacture of a medicament for the treatment of a condition which is mediated by the action of PGE2 at EP4 receptors.
According to another embodiment of the invention there is provided the use of a compound of the invention or a pharmaceutically acceptable derivative thereof for the manufacture of a medicament for the treatment or prevention of a condition such as a pain, inflammatory, immunological, bone, neurodegenerative or renal disorder.
The compounds of the invention and their pharmaceutically acceptable derivatives are conveniently administered in the form of pharmaceutical compositions. Such compositions may conveniently be presented for use in conventional manner in admixture with one or more physiologically acceptable carriers or excipients.
Thus, in another aspect of the invention, there is provided a pharmaceutical composition comprising a compound of the invention or a pharmaceutically acceptable derivative thereof adapted for use in human or veterinary medicine.
While it is possible for the compounds of the invention or a pharmaceutically acceptable derivative thereof to be administered as the raw chemical, it is preferable to present it as a pharmaceutical formulation. The formulations of the present invention comprise the compounds of the invention or a pharmaceutically acceptable derivative thereof together with one or more acceptable carriers or diluents therefor and optionally other therapeutic ingredients. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
The formulations include those suitable for oral, parenteral (including subcutaneous e.g. by injection or by depot tablet, intradermal, intrathecal, intramuscular e.g. by depot and intravenous), rectal and topical (including dermal, buccal and sublingual) administration although the most suitable route may depend upon for example the condition and disorder of the recipient. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy, (see for example methods disclosed in 'Remington - The Science and Practice of Pharmacy', 21st Edition, Lippincott, Williams & Wilkins, USA, 2005 and references therein). All methods include the step of bringing into association the compound of the invention or a pharmaceutically acceptable acid addition salt thereof ("active ingredient") with the carrier which constitutes one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation. Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets (e.g. chewable tablets in particular for paediatric administration) each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste.
A tablet may be made by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating, surface active or dispersing agent. Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein.
Formulations for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of a sterile liquid carrier, for example, water-for-injection, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described. Formulations for rectal administration may be presented as a suppository with the usual carriers such as cocoa butter, hard fat or polyethylene glycol.
Formulations for topical administration in the mouth, for example buccally or sublingually, include lozenges comprising the active ingredient in a flavoured basis such as sucrose and acacia or tragacanth, and pastilles comprising the active ingredient in a basis such as gelatin and glycerin or sucrose and acacia.
The compounds of the invention may also be formulated as depot preparations. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds of the invention may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
In addition to the ingredients particularly mentioned above, the formulations may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavouring agents.
The EP4 receptor compounds for use in the present invention may be used in combination with other therapeutic agents, for example COX-2 inhibitors, such as celecoxib, rofecoxib, valdecoxib or parecoxib; 5-lipoxygenase inhibitors; analgesics such as paracetamol; NSAID's, such as diclofenac, indomethacin, nabumetone, naproxen or ibuprofen; leukotriene receptor antagonists; DMARD's such as methotrexate; sodium channel blockers, such as lamotrigine; N-type calcium channel antagonists; NMDA receptor modulators, such as glycine receptor antagonists; gabapentin, pregabalin and related compounds; tricyclic antidepressants such as amitriptyline; neurone stabilising antiepileptic drugs; mono-aminergic uptake inhibitors such as venlafaxine; opioid analgesics; local anaesthetics; 5HTi agonists, such as triptans, for example sumatriptan, naratriptan, zolmitriptan, eletriptan, frovatriptan, almotriptan or rizatriptan; EPi receptor ligands; EP2 receptor ligands; EP3 receptor ligands; EPi antagonists; EP2 antagonists and EP3 antagonists; cannabanoid receptor agonists; VR1 antagonists. When the compounds are used in combination with other therapeutic agents, the compounds may be administered either sequentially or simultaneously by any convenient route.
The invention thus provides, in a further embodiment, a combination comprising a compound of the invention or a pharmaceutically acceptable derivative thereof together with a further therapeutic agent or agents. In one embodiment of the invention there is provided a combination comprising a compound of the invention or a pharmaceutically acceptable derivative thereof and paracetamol.
The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation and thus pharmaceutical formulations comprising a combination as defined above together with a pharmaceutically acceptable carrier or excipient comprise a further aspect of the invention. In particular there is provided a pharmaceutical composition comprising a compound of the invention or a pharmaceutically acceptable derivative thereof, paracetamol and a pharmaceutically acceptable carrier or diluent therefor. The individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations.
When a compound of the invention or a pharmaceutically acceptable derivative thereof is used in combination with a second therapeutic agent active against the same disease, the dose of each compound may differ from that when the compound is used alone. Appropriate doses will be readily appreciated by those skilled in the art.
A proposed daily dosage of a compound of the invention, or a pharmaceutically acceptable salt thereof, for the treatment of man is from 0.001 to 30 mg/kg body weight per day and more particularly 0.1 to 3 mg/kg body weight per day, calculated as the free acid, which may be administered as a single or divided dose, for example one to four times per day. The dose range for adult human beings is generally from 0.1 to 1000 mg/day, such as from 10 to 800 mg/day, preferably 10 to 200 mg/day, calculated as the free acid.
A suitable daily dosage of paracetamol is up to 4000 mg per day. Suitable unit doses include 200, 400, 500 and 1000 mg, one, two, three or four times per day.
The precise amount of the compounds of the invention administered to a host, particularly a human patient, will be the responsibility of the attendant physician. However, the dose employed will depend on a number of factors including the age and sex of the patient, the precise condition being treated and its severity, the route of administration, and any possible combination therapy that may be being undertaken.
The compounds of the invention may be prepared according to Schemes 1a, 1b and 1c in which they are denoted generally as "Formula (I)".
Scheme 1a
Figure imgf000020_0001
where, (i) LHMDS, THF; (ii) R-Br or R-I, K2CO3, (CH3)2CO; (iii) NaOH1 EtOH/H2O; (iv) SOCI2, CHCI3; (v) CH3CO2H; (vi) Pd/C, H2, EtOH; (vii) NaBH4, MeOH/THF or EtOH/THF; (viii) Et3SiH, TFA. As used in Schemes 1a, 1b and 1c,
R1 represents Ci-4 alkyl;
R represents Ci-4 alkyl or CH2Ph;
R2 and R3 independently represent Ci-4 alkyl or CH2Ph;
R4 represents Ci-4 alkyl, Ci-4 alkoxy or CF3;
R5 represents C1-6 alkyl;
R6 represents Ci-4 alkyl; m and n independently represent 0 or 1 ; and
R* = R3 or R6.
In Scheme 1a, where R2 and R3 are different step ii is carried out as a two step process in which R2 is added and then R3, or vice versa.
Scheme 1b
Figure imgf000021_0001
Formula (I)
Figure imgf000021_0002
Figure imgf000021_0003
Formula (I)
Formula (I)
Figure imgf000021_0004
where, (ix) glacial acetic acid, 2N HCI (1 :1); (x) NaBH4, MeOH/THF; (xi) Et3SiH, TFA.
Scheme 1c
Figure imgf000022_0001
Formula (I)
where, (xii) NaOH, EtOH.
As used herein, the term 'Ch alky!' includes straight chain and branched chain alkyl groups containing 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, iso- propyl, n-butyl, /so-butyl and tert-butyl. The term 'Ci-6 alkyl' may be interpreted accordingly.
Compounds of formula (1) are commercially available or may be prepared in accordance with methods known in the art. For example, methyl dimethylphthalate may be purchased from Sigma-Aldrich Co. Ltd.
Compounds of formula (A) are commercially available or may be prepared in accordance with methods known in the art. For example, diethyl succinate may be purchased from Sigma-Aldrich Co. Ltd. The reaction between compounds of formula (1) and compounds of formula (A) may be performed in accordance with the method disclosed in International Patent Application, Publication Number WO 02/064564.
Compounds of formula (B) may be prepared according to Scheme 2:
Scheme 2
Figure imgf000023_0001
where, (i) NaH, dry DMF or DMSO; (ii) NH4CO2H, EtOH, Pd/C; or Pd/C, H2 followed by NaOH, then HCI, then EtOH/PhMe/PTSA; wherein R4 and R5 are as defined in relation to Schemes 1a, 1 b and 1c and R7 represents Ci-4 alkyl or CH2Ph.
As used in Scheme 2, X represents halo, for example F or Cl.
Compounds of formula (4) are commercially available or may be prepared in accordance with methods known in the art. For example, 5-fluoro-2- nitrobenzeneotrifluoride and 5-fluoro-2-nitrotoluene and 5-chloro-2-nitroanisole may be purchased from Sigma-AIdrich Co. Ltd.
Compounds of formula (5) are commercially available or may be prepared in accordance with methods known in the art. For example, benzyl ethyl malonate and dimethyl malonate may be purchased from Sigma-AIdrich Co. Ltd.
The following Descriptions and Examples illustrate the preparation of the compounds of the invention. Descriptions refer to intermediate compounds.
Abbreviations
DCM Dichloromethane
DMAP 4-(Dimethylamino)pyridine
DMSO Dimethylsulfoxide
EtOAc Ethyl acetate
EtOH Ethanol
DMF Dimethylformamide
HCI Hydrochloric acid
LC/MS Liquid chromatography/Mass spectroscopy
LHMDS Lithium hexamethyldisylazide .
MeOH Methanol
MDAP Mass directed auto preparation
PTSA p-toluene sulfonic acid
TFA Thfluoroacetic acid
THF Tetrahydrofuran
Analytical procedures
LC/MS
Column
Waters Atlantis (4.6mm x 50mm). Stationary phase particle size, 3μtn.
Solvents
A: Aqueous solvent = Water + 0.05% Formic Acid B: Organic solvent = Acetonithle + 0.05% Formic Acid
Method
Time / min %B
0 3
0.1 3
4 97
4.8 97
4.9 3
5.0 3
• Flow rate, 3ml/mins. • Injection volume, 5μl.
• Column temperature, 3O0C.
• UV detection range, 220 to 330nm.
All retention times are measured in minutes.
Purification Techniques
Purification of the Examples may be carried out by conventional methods such as chromatography and/or recrystallisation using suitable solvents. Chromatographic methods include column chromatography, flash chromatography, HPLC (high performance liquid chromatography), SFC
(supercritical fluid chromatography), and MDAP (mass directed autopreparation).
The term "Biotage" when used herein refers to commercially available prepacked silica gel cartridges.
Mass Directed Auto Preparation (MDAP)
Column
Waters Atlantis: 19mm x 100mm (small scale); and 30mm x 100mm (large scale). Stationary phase particle size, 5μm. Solvents
A: Aqueous solvent = Water + 0.1% Formic Acid B: Organic solvent = Acetonitrile + 0.1 % Formic Acid Make up solvent = Methanol : Water 80:20 Needle rinse solvent = Methanol
Methods
Five methods were used depending on the analytical retention time of the compound of interest:
(1) Large/Small Scale 1.0-1.5 = 5-30% B
(2) Large/Small Scale 1.5-2.2 = 15-55% B
(3) Large/Small Scale 2.2-2.9 = 30-85% B (4) Large/Small Scale 2.9-3.6 = 50-99% B
Runtime, 13.5 minutes, comprising 10-minute gradient followed by a 3.5 minute column flush and re-equilibration step.
(5) Large/Small Scale 3.6-5.0 = 80-99% B
Runtime, 13.5 minutes, comprising 6-minute gradient followed by a 7.5 minute column flush and re-equilibration step.
Flow rate
20mls/min (Small Scale) or 40mls/min (Large Scale).
Supercritical Fluid Chromatography (SFC)
Berger Ethyl-Pyridine column (150mm x 21.2 mm ID; 6 micron ) A= Carbon dioxide and B = Methanol
Isocratic ® A:B ( 85:15 v/v ); Flow = 50ml_min-1 ; 35 °C; 100 bar Detection by U. V. absorbance at 220 nm Injection volume: 25OuL
Chiral Supercritical Fluid Chromatography (SFC)
Chiralcel OD ( 250mm x 20mm ID; 10 micron ) A= Carbon dioxide and B = Methanol lsocratic @ A:B ( 75:25 v/v); Flow = 50mLmin-1 ; 35 °C; 100 bar Detection by U.V. absorbance at 215 nm Injection volume: 1 mL
High Performance Liquid Chromatography (HPLC)
Chiralcel OD (250mm x 20 mm ID; 10 micron) A = Heptane and B = EtOH lsocratic @ A: B (70:30 v/v); Ambient temperature. Detection by U.V. absorbance at 215 nm
ID = internal diameter
Description 1
Diethyl 1, 4-dihydroxy-6-methyl-2, 3-naphthalenedicarboxylate
Figure imgf000029_0001
Methyl dimethylphthalate(10g, 48mmol) and LHMDS (1 M in hexanes, 196ml, 192mmol) in THF (150ml) were cooled to O0C. Diethyl succinate (15.9ml, 96mmol) was added dropwise over 20 minutes (maximum internal temperature 4 0C). Allowed to warm to room temperature. After 4 hours, 1 M HCI (~500ml) was added and the aqueous was extracted with EtOAc (x2), all the combined organics washed with brine, dried over magnesium sulphate and concentrated in vacuo to give an orange oil. This was purified by chromatography on silica gel eluting with ethyl acetate/hexane (2:98) to yield the title compound as a white solid (3.03g, 9.5mmol). LC/MS: Rt=3.51.
Description 2
Diethyl 1, 4-bis(propyloxy)-2, 3-naphthalenedicarboxylate
Figure imgf000029_0002
1-Bromopropane (13.1ml, 144.4mmol) was added to a stirring solution of diethyl 1 ,4-dihydroxy-2, 3-naphthalenedicarboxylate* (11g, 36.1mmol) and potassium carbonate (24.9g, 180.5mmol) in acetone (180ml). Refluxed overnight under an atmosphere of argon. The resulting mixture was cooled, filtered and the solvent evaporated from the filtrate. The residue was taken up in toluene and washed with 5% potassium hydroxide solution, brine and dried over magnesium sulphate. Purified by chromatography on silica gel eluting with ethyl acetate/hexane (1 :9) to give the title compound as yellow oil (11.45g, 29.5mmol). LC/MS: Rt=3.87, [MH]+ 389.
*1 ,4-dihydroxy-2,3-naphthalenedicarboxylate may be prepared in accordance with the method disclosed in International Patent Application, Publication Number WO02/064564.
The following compounds were prepared in a similar manner to diethyl 1 ,4- bis(propyloxy)-2,3-naphthalenedicarboxylate using the appropriate starting materials.
Figure imgf000030_0002
Description 6
1, 4-Bis(propyloxy)-2, 3-naphthalenedicarboxylic acid
Figure imgf000030_0001
A mixture of diethyl 1 ,4-bis(propyloxy)-2,3-naphthalenedicarboxylate (11.45g, 29.5mmol), ethanol (70ml), sodium hydroxide (3.54g, 88.5mmol) and water (15ml) was refluxed for 4 hours. The reaction mixture was cooled and evaporated to a third of the volume. This was acidified with hydrochloric acid (2N) and extracted with ethyl acetate (3x 100ml). Combined organics washed with water, brine and dried over magnesium sulphate. Solvent was evaporated to give the title compound as a yellow solid (8.91 g, 26.8mmol). LC/MS: Rt=2.74, [MH]+ 333.
The following compounds were prepared in a similar manner to 1 ,4- bis(propyloxy)-2,3-naphthalenedicarboxylic acid using the appropriate starting materials.
Figure imgf000031_0001
Description 10
4, 9-Bis(propyloxy)naphtho[2, 3-c]furan- 1, 3-dione
Figure imgf000032_0001
Thionyl chloride (20.5ml, 281.4mmol) was added dropwise to a solution of 1 ,4- bis(propyloxy)-2,3-naphthalenedicarboxylic acid (8.91 g, 26.8mmol) in chloroform (80ml) and heated at 650C for 2.5 hours. The reaction mixture was cooled and solvent evaporated to yellow solid. Azeotroped with chloroform to give the title compound as a beige solid (8.74g, 103% yield). LC/MS: Rt=3.77, [MH]+ 315.
The following compounds were prepared in a similar manner to 4,9- bis(propyloxy)naphtho[2,3-c]furan-1 , 3-dione using the appropriate starting materials.
Figure imgf000032_0002
Description 13
Dimethyl [3-(methyloxy)-4-nitrophenyl]propanedioate
Figure imgf000033_0001
Sodium hydride (60% in oil, 8.73g, 2.2eq) was washed with 40-60 petroleum ether (x2) then DMSO (225ml) was added followed by dimethylmalonate (25ml, 2.2eq) in portions. After addition the mixture was heated to 1000C for 30 minutes then cooled to room temperature overnight. The next day, 5-chloro-2-nitroanisole (18.61g, 1eq) was added and the solution heated to 1000C (internal). After 3 hours further sodium malonate (0.6eq) {dimethylmalonate (6.8ml) and sodium hydride (2.38g) in DMSO (60ml)} was added, plus further 5-chloro-2-nitroanisole (2.71g) and further dimethylmalonate (4ml). After 17 hours heating, the solution was cooled; acetic acid (18ml) added and then poured onto water (700ml) in portions. Extracted with diethyl ether/petroleum ether 40-60 (1 :1 , 4x140ml), then with DCM/cyclohexane (2:1). Organics combined and excess dimethyl malonate distilled off in vacuo to give a dark red oil (~30g). Purified by silica gel chromatography (DCM) to give oil (~20.4g) which was further purified twice by silica gel chromatography (CHCI3, then DCM) to give the title compound as a yellow solid (11.56g).
Description 14
Ethyl [4-amino-3-(methyloxy)phenyl]acetate
Figure imgf000033_0002
Dimethyl [3-(methyloxy)-4-nitrophenyl]propanedioate (19.65g) and 10% Pd on charcoal (1.3g) was stirred under hydrogen in a mix of EtOH, acetic acid and CHCI3 (400ml). After a few hours, concentrated HCI (4ml) was added and the mixture stirred under hydrogen overnight. The catalyst was filtered and EtOH (250ml) added, followed by NaOH (6.3g) in water (60ml) to give a dark solution (solvents had been degassed with N2). Stood at room temperature for 2 days then diluted with further EtOH and acidified with concentrated HCI. Heated under reflux for 2 hours, then evaporated in vacuo to dryness, water (350ml) added and extracted with CHCI3 (x3). Organics evaporated in vacuo to dryness, treated with aqueous NaOH over the weekend at room temperature, evaporated to dryness again, aqueous HCI added and heated at 900C for 75 minutes, before evaporating to dryness again. Isolation of acid proved difficult, so ethyl ester was formed: all aqueous fractions were combined, evaporated to dryness, then suspended in a mixture of toluene (40ml) and EtOH (140ml) with toluene sulfonic acid (catalyst) and heated under reflux with a Dean Stark head attached for 7 hours. Cooled and evaporated in vacuo, water added, then basified with solid NaHCO3. Extracted with CHCI3 and evaporated in vacuo to give a black oil (6.9g). Purified by silica gel chromatography (DCM) to give a brown oil (3.78g). Treated in CHCI3 with HCI in dioxane and evaporated to dryness to give the title compound as the HCI salt (4.21 g). LC/MS: Rt=2.15, [M+] 209.
Description 15
Ethyl phenylmethyl [4-nitro-3-(trifluoromethyl)phenyl]propanedioate
Figure imgf000034_0001
Sodium hydride (382mg, 9.6mmol) was added portionwise to an ice bath chilled solution of benzyl ethyl malonate (2.1g, 9.6mmol) in dry DMF (20ml) and stirred for 10 minutes. At room temperature 5-fluoro-2-nitrobenzenotrifluoride (2g, 9.6mmol) was added and stirred under argon. Heated at 1000C overnight. The reaction mixture was cooled and partitioned between 2N hydrochloric acid (75ml) and ethyl acetate (75ml). The aqueous layer was extracted with ethyl acetate (2x 75ml) and the combined organics were evaporated to a yellow oil. Purified by chromatography on silica gel eluting with ethyl acetate/hexane (1 :4) to give the title compound as a yellow oil (1.23g, 3.0mmol). LC/MS: Rt=3.53, [MH]" 410.
The following compound was prepared in a similar manner to ethyl phenylmethyl [4-nitro-3-(trifluoromethyl)phenyl]propanedioate using the appropriate starting materials.
Figure imgf000035_0001
Description 17
Ethyl [4-amino-3-(trifluoromethyl)phenyl]acetate
Figure imgf000035_0002
Ethyl phenylmethyl [4-nitro-3-(trifluoromethyl)phenyl]propanedioate (2.1g, δ.Ommol) dissolved in ethanol (30ml), was treated with ammonium formate (3.16g, 50.1 mmol) and palladium on carbon 10% paste (200mg) was added under argon. The reaction mixture was refluxed for 3 hours, cooled and filtered. Evaporated and purified by chromatography on silica gel eluting with ethyl acetate/hexane (1 :4) to give the title compound as a yellow oil (490mg,1.98mmol). LC/MS: Rt=2.70, [MH]+ 248. The following compound was prepared in a similar manner to ethyl [4-amino-3- (trifluoromethyl)phenyl]acetate, using the appropriate starting materials.
Figure imgf000036_0002
Description 19
Ethyl {4-[1 ,3-dioxo-4,9-bis(propyloxy)-1 ,3-dihydro-2H-benzo[/]isoindol-2-yl]-3- methylphenyl}acetate
Figure imgf000036_0001
4,9-Bis(propyloxy)naphtho[2,3-c]furan-1 ,3-dione (200mg, O.θmmol) dissolved in acetic acid (2ml), was treated with ethyl (4-amino-3-methylphenyl)acetate (245mg, 1.2mmol) and heated at reflux overnight. The reaction mixture was cooled and diluted with ethyl acetate and water. Aqueous phase was extracted with ethyl acetate (x2). Combined organics were washed with brine and dried over magnesium sulphate. Evaporated and purified by chromatography on silica gel eluting with ethyl acetate/hexane (1 :5) to give an orange oil, which was triturated in methanol to give the title compound as a white solid (264mg, O.δmmol). LC/MS: Rt= 4.13, [MH]+ 490. The following compounds were prepared in a similar manner to ethyl {4-[1 ,3- dioxo-4,9-bis(propyloxy)-1 ,3-dihydro-2H-benzo[flisoindol-2-yl]-3- methylphenyl}acetate using the appropriate starting materials. Some of these compounds were prepared in the presence of DMAP and powdered molecular sieves (4A) to drive the reactions to completion, then purified with a recrystallisation from isopropanol (denoted by *).
Figure imgf000037_0001
Figure imgf000038_0002
Description 24
Ethyl {4-[4,9-bis(ethyloxy)-6-methyl-1 ,3-dioxo-1 ,3-dihydro-2H-benzo[f)isoindol-2- yl]phenyl}acetate
Figure imgf000038_0001
i ^-BisCethyloxyJ-δ-methyl^.S-naphthalenedicarboxylic acid (0.1g, 0.3mmol), ethyl (4-aminophenyl)acetate (130mg, 0.63mmol) and 4A powdered molecular sieves (120mg) were suspended in N-methylpyrrolidine (1ml) in a microwave vial, sealed and heated in a microwave at 15O0C for 30 minutes. Cooled, diluted with EtOAc and washed with water. The aqueous was extracted with further EtOAc. The combined organics were washed with 2M HCI, brine, dried (MgSO4), and concentrated in vacuo. Chromatography purification was carried out (1Og Siθ2, elution with 5-30%EtOAc in hexanes) to yield the title compound as an off white solid (105mg, 75%). LC/MS: Rt=3.88, [MH]+ 462. Example 1
{4-[1, 3-Dioxo-4, 9-bis(propyloxy)-1 , 3-dihydro-2H-benzo[f]isoindol-2-yl]-3- methylphenyl}acetic acid
Figure imgf000039_0001
Ethyl {4-[1 ,3-dioxo-4,9-bis(propyloxy)-1 ,3-dihydro-2H-benzo[/]isoindol-2-yl]-3- methylphenyljacetate (39mg, O.Oδmmol) was suspended in glacial acetic acid (2ml) and 2N hydrochloric acid (2ml), and heated until complete, (50-1100C, for 70 hours). Cooled and water was added. The white precipitate which formed was filtered, washed with water, collected and dried in a vacuum oven overnight. (15mg, 0.03mmol) LC/MS: Rt=3.71 , [MH]+ 462.
The following compounds were prepared in a similar manner to {4-[1 ,3-dioxo-4,9- bis(propyloxy)-1 ,3-dihydro-2H-benzo[f]isoindol-2-yl]-3-methylphenyl}acetic acid using the appropriate staring materials. Some of the final compounds required MDAP purification (denoted by *). Where no precipitate was formed on addition of water, an ethyl acetate extraction was achieved to recover the final product (denoted by #)
Figure imgf000039_0002
Figure imgf000040_0001
Description 25
Ethyl {4-[1-hydroxy-3-oxo-4, 9-bis(propyloxy)-1,3-dihydro-2H-benzo[f]isoindol-2- yl]-3-methylphenyl}acetate
Figure imgf000040_0002
Ethyl {4-[1 ,3-dioxo-4,9-bis(propyloxy)-1 ,3-dihydro-2H-benzo[/]isoindol-2-yl]-3- methylphenyl}acetate (200mg, 0.4mmol) was suspended in methanol (3ml) and tetrahydrofuran (1ml) added to the solution. Cooled to O0C in an ice bath and treated with sodium borohydride (46mg, 1.22mmol) portionwise over 2 minutes. Stirred under argon for 1 hour at O0C. Solvent evaporated and the residue was partitioned between ethyl acetate and 1 M ammonium chloride solution. The aqueous layer was extracted with ethyl acetate (x2). Combined organics washed with brine and dried over magnesium sulphate. Organics evaporated to give the title compound (215mg, 0.43mmol) LC/MS: Rt=3.70, [MH]+ 492.
The following compounds were prepared in a similar manner to.ethyl {4-[1- hydroxy-3-oxo-4,9-bis(propyloxy)-1 ,3-dihydro-2H-benzo[/]isoindol-2-yl]-3- methylphenyljacetate using the appropriate starting materials. Some compounds were prepared in the presence of ethanol to accelerate the reaction (denoted by *).
Figure imgf000041_0001
Description 28
Ethyl {3-methyl-4-[1-oxo-4,9-bis(propyloxy)-1,3-dihydro-2H-benzo[f]isoindol-2- yl]phenyl}acetate
Figure imgf000042_0001
Ethyl {4-[1 -hydroxy-3-oxo-4,9-bis(propyloxy)-1 ,3-dihydro-2/-/-benzo[/]isoindol-2- yl]-3-methylphenyl}acetate (215mg, 0.4mmol) was dissolved in trifluoroacetic acid (3ml) and cooled in an ice bath to O0C. Treated with triethylsilane (0.10ml, 0.65mmol) and stirred at O0C for 1 hour. Volatiles evaporated and purified directly by chromatography on silica gel eluting with ethyl acetate/hexane (1 :4). MDAP purification followed to give the title compound as a white solid (29mg, O.Oδmmol). LC/MS: Rt=4.05, [MH]+ 476.
The following compounds were prepared in a similar manner to ethyl {3-methyl-4- [1 -oxo-4, 9-bis(propyloxy)-1 ,3-dihydro-2/-/-benzo[/]isoindol-2-yl]phenyl}acetate using the appropriate starting materials.
Figure imgf000042_0002
Figure imgf000043_0002
Example 6
{3-Methyl-4-[1-oxo-4,9-bis(propyloxy)-1,3-dihydro-2H-benzo[f]isoindol-2- yl]phenyl}acetic acid
Figure imgf000043_0001
Ethyl {3-methyl-4-[1 -oxo-4,9-bis(propyloxy)-1 ,3-dihydro-2H-benzo[^Jisoindol-2- yl]phenyl}acetate (29mg, 0.06mmol) was dissolved in ethanol (3ml) and treated with 2N sodium hydroxide (1ml). Heated to reflux for two hours then cooled, and the solvent evaporated. The residue was acidified with 2N hydrochloric acid to pH1. The solid precipitate was filtered, washed with water and dried in a vacuum oven overnight, to give the title compound as a white solid (23mg, O.Oδmmol). LC/MS: Rt=3.61 , [MH]+ 448.
The following compounds were prepared in a similar manner to {3-methyl-4-[1- oxo-4, 9-bis(propyloxy)-1 ,3-dihydro-2H-benzo[/]isoindol-2-yl]phenyl}acetic acid using the appropriate starting materials.
Figure imgf000044_0002
Description 31
Diethyl 1-(ethyloxy)-4-hydroxy-2, 3-naphthalenθdicarboxylate
Figure imgf000044_0001
Bromoethane (0.359g, 3.29mmol) was added to a stirred solution of diethyl 1 ,4- dihydroxy-2,3-naphthalenedicarboxylate (1g, 3.29mmol) and potassium carbonate (0.454g, 3.29mmol) in acetone (25ml). The reaction mixture was refluxed for 24 hours under an atmosphere of argon. The resulting mixture was evaporated and the residue was partitioned between 2 x ethylacetate and water. The combined organics were washed with water and dried over magnesium sulphate. The orange oil was purified by chromatography on silica gel, eluting with ethyl acetate (0-10%) in hexane to give the title compound as a clear oil (0.661g, 1.99mmol). LC/MS: Rt=3.63, [MH]" 331. The following compounds were prepared in a similar manner to diethyl 1- (ethyloxy)-4-hydroxy-2,3-naphthalenedicarboxylate using the appropriate alkylating agent, methyl iodide and 2-bromo propane.
Figure imgf000045_0002
Description 34
Diethyl 1-(ethyloxy)-4-[(phenylmethyl)oxy]-2,3-naphthalenedicarboxylate
Figure imgf000045_0001
Benzyl bromide (1.32ml, 11.1mmol) was added to a stirred solution of diethyl 1- (ethyloxy)-4-hydroxy-2,3-naphthalenedicarboxylate (2.45g, 7.38mmol) and potassium carbonate (1.53g, 11.1mmol) in acetone (50ml). The reaction mixture was refluxed for 1 hour under an atmosphere of argon. The resulting mixture was evaporated and the residue was partitioned between 2 x ethylacetate and brine. The combined organics were washed with water and dried over magnesium sulphate. The clear oil was purified by chromatography on silica gel, eluting with ethyl acetate (0-40%) in hexane to give the title compound as clear oil (3.05g, 7.23mmol). LC/MS: Rt=3.77, [MH]+ 423.
The following compounds were prepared in a similar manner to diethyl 1- (ethyloxy)-4-[(phenylmethyl)oxy]-2,3-naphthalenedicarboxylate using the appropriate starting materials.
Description Name LC/MS
35 Diethyl 1-(methyloxy)-4- Rt=3.80 [(phenylmethyl)oxy]-2,3- [MH]+409 naphthalenedicarboxylate
36 Diethyl 1-[1- Rt=3.83 methylethoxy]-4- [MNH3J+ [(phenylmethyl)oxy]-2,3- 454 naphthalenedicarboxylate
Figure imgf000046_0001
Description 37
1-(Ethyloxy)-4-[(phenylmethyl)oxy]-2,3-naphthalenedicarboxylic acid
Figure imgf000046_0002
A mixture of diethyl 1-(ethyloxy)-4-[(phenylmethyl)oxy]-2,3- naphthalenedicarboxylate (3.05g, 7.23mmol), ethanol (30ml), and 2N aqueous sodium hydroxide solution (35ml) was refluxed for 3 hours. The reaction mixture was cooled and evaporated. This was acidified with HCI (2N) and extracted with 2 x ethyl acetate. Combined organics were dried over magnesium sulphate and the solvent evaporated to give the title compound as a white solid (2.55g, 6.97mmol). LC/MS: Rt=2.76, [MH]" 365.
The following compounds were prepared in a similar manner to 1 -(ethyloxy)-4- [(phenylmethyl)oxy]-2,3-naphthalenedicarboxylic acid using the appropriate starting materials.
Figure imgf000047_0001
Description 40
Ethyl (4-{4-(ethyloxy)-1,3-dioxo-9-[(phenylmethyl)oxy]-1,3-dihydro-2H- benzo[f]isoindol-2- yl}phenyl)acetate
Figure imgf000047_0002
A mixture of 1-(ethyloxy)-4-[(phenylmethyl)oxy]-2,3-naphthalenedicarboxylic acid (2.55g, 6.97mmol) and ethyl (4-aminophenyl)acetate (2.49g, 13.9mmol) were heated to 1200C in acetic acid (20ml) for 18 hours. The reaction mixture was diluted with brine and extracted with 2 x ethyl acetate. Combined organics were washed with water then dried over magnesium sulphate, the solvent evaporated to give a brown oil. This was purified by chromatography on silica gel, eluting with ethyl acetate (0-30%) in hexane to give the title compound as a peach coloured solid (2.63g, 5.17mmol). LC/MS: Rt=3.95, [MH]+ 510.
The following compounds were prepared in a similar manner to ethyl (4-{4- (ethyloxy)-1 ,3-dioxo-9-[(phenylmethyl)oxy]-1 ,3-dihydro-2/-/-benzo[r]isoindol-2- yl}phenyl)acetate using the appropriate starting materials.
Figure imgf000048_0001
Example 9
(4-{4-(Ethyloxy)- 1, 3-dioxo-9-[(phenylmethyl)oxyJ- 1, 3-dihydro-2H-benzo[f]isoindol- 2-yl}phenyl)acetic acid
Figure imgf000049_0001
Ethyl (4-{4-(ethyloxy)-1 ,3-dioxo-9-[(phenylmethyl)oxy]-1 ,3-dihydro-2H- benzo[/Jisoindol-2- yl}phenyl)acetate (0.1Og, 0.196mmol) was heated to 1000C in a 1 :1 mixture of acetic acid : 2N aqueous hydrochloric acid (8ml) for 1 hour. The reaction was cooled to room temperature. On addition of water, the resulting yellow solid was collected by filtration and washed with water. This was purified by MDAP to give the desired product (0.017g, 0.035mmol). LC/MS: Rt=3.46, [MH]+ 482.
Description 43
Ethyl (4-{4-hydroxy-9-[1-methylethoxy]- 1, 3-dioxo- 1, 3-dihydro-2H-benzo[f]isoindol- 2-yl}phenyl)acetate
Figure imgf000049_0002
10% Palladium on carbon (0.365g) was suspended in ethanol (500ml), to this was added ethyl (4-{4-[1-methylethoxy]-1 ,3-dioxo-9-[(phenylmethyl)oxy]-1 ,3- dihydro-2H-benzo[/]isoindol-2-yl}phenyl)acetate (3.65g, 6.98mmol). The reaction was stirred at room temperature under an atmosphere of hydrogen for 3 hours. This was filtered through a bed of celite under a blanket of argon, and washed with ethanol and dichloromethane. The filtrate was evaporated to give an orange solid (3.05g, 7.04mmol). LC/MS: Rt=3.72, [MH]+ 434.
The following compounds were prepared in a similar manner to ethyl (4-{4- hydroxy-9-[1 -methylethoxy]-1 ,3-dioxo-1 ,3-dihydro-2H-benzo[/]isoindol-2- yl}phenyl)acetate using the appropriate starting materials.
Figure imgf000050_0001
Description 46
Ethyl (4-{4-[(-[1-methylethoxy]-9-[(2-methylpropyl)oxy]-1 ,3-dioxo-1 ,3-dihydro-2H- benzo[f]isoindol-2- yl}phenyl)acetate
Figure imgf000051_0001
To a solution of ethyl (4-{4-hydroxy-9-[1-methylethoxy]-1 ,3-dioxo-1 ,3-dihydro-2/-/- benzo[/]isoindol-2-yl}phenyl)acetate (0.3Og, 0.693mmols) in dimethylformamide (5ml), was added potassium carbonate (0.191g, 1.39mmol) followed by 1-bromo- 2-methylpropane (0.192g, 1.04mmol). The reaction was heated to 8O0C for 6 hours. A further addition of 1-bromo-2-methylpropane (0.192g, 1.04mmol) was made and heating continued for a further 4 hours. The cooled mixture was partitioned between 2x ethyl acetate and brine, the combined organics were washed with water, dried over sodium sulphate and evaporated down to a yellow oil. This was purified by chromatography on silica gel, eluting with ethyl acetate (0-30%) in hexane to give the title compound as a yellow coloured solid (0.225g, 0.460mmol). LC/MS: Rt=4.07, [MH]+ 490.
The following compounds were prepared in a similar manner to ethyl (4-{4-[(-[1- methylethoxy]-9-[(2-methylpropyl)oxy]-1 ,3-dioxo-1 ,3-dihydro-2H-benzo[/]isoindol- 2- yl}phenyl)acetate using the appropriate starting materials.
Figure imgf000052_0001
Figure imgf000053_0001
10 Example 10
(4-{4-[1-Methylethoxy]-9-[(2-methylpropyl)oxy]-1,3-dioxo-1,3-dihydro-2H- benzo[f]isoindol-2-yl}phenyl)acetic acid
Figure imgf000054_0001
Ethyl (4-{4-[(-[1-methylethoxy]-9-[(2-methylpropyl)oxy]-1 ,3-dioxo-1 ,3-dihydro-2H- benzo[/]isoindol-2- yl}phenyl)acetate (0.225g, 0.460mmol) was heated to 1000C in a 1 :1 mixture of acetic acid : 2N aqueous hydrochloric acid (10ml) for 2 hours. The reaction was cooled to room temperature. On addition of water, the resulting yellow solid was collected by filtration and washed with water to give 0.2Og of crude product. 0.10g was purified by mass directed autoprep to give the title compound (0.076g, 0.165mmol). LC/MS: Rt=3.73, [MH]+ 462.
The following compounds were prepared in a similar manner to (4-{4-[1- methylethoxy]-9-[(2-methylpropyl)oxy]-1 ,3-dioxo-1 ,3-dihydro-2/-/-benzo[/]isoindol- 2-yl}phenyl)acetic acid using the appropriate starting materials.
Figure imgf000055_0001
Figure imgf000056_0002
Description 54
{4-[4-(Butyloxy)-9-(ethyloxy)-3-hydroxy-1 -oxo-1, 3-dihydro-2H-benzo[f]isoindol-2- yl]phenyl}acetic acid and {4-[4-(butyloxy)-9-(ethyloxy)-1-hydroxy-3-oxo-1,3- dihydro-2H-benzo[f]isoindol-2-yl]phenyl}acetic acid
Figure imgf000056_0001
To a solution of {4-[4-(butyloxy)-9-(ethyloxy)-1 ,3-dioxo-1 ,3-dihydro-2H- benzo[/]isoindol-2-yl]phenyl}acetic acid (0.16Og, 0.358mmol) in ethanol (3ml) and tetrahydrofuran (3ml) cooled to O0C, was added sodium borohydride (0.041 g, 1.17mmol) portion wise. The reaction was stirred at O0C for 1 hour then a further portion of sodium borohydride (0.041g, 1.17mmol) was added, stirring continued at room temperature for 1 hour. The mixture was evaporated and then quenched with aqueous saturated ammonium chloride solution. This was extracted x 2 with ethyl acetate. The aqueous phase was acidified with 2N hydrochloric acid and then re-extracted x 2 with ethyl acetate. The combined organics were washed with brine, dried over magnesium sulphate and evaporated to give the crude product (0.168g, 0.374mmol). LC/MS: Rt=3.26, [MH]+450.
The following compounds were prepared in a similar manner to {4-[4-(butyloxy)- 9-(ethyloxy)-3-hydroxy-1-oxo-1 ,3-dihydro-2H-benzo[/]isoindol-2-yl]phenyl}acetic acid and {4-[4-(butyloxy)-9-(ethyloxy)-1-hydroxy-3-oxo-1 ,3-dihydro-2/-/- benzo[/]isoindol-2-yl]phenyl}acetic acid using the appropriate starting materials.
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
Description 59
Ethyl (4-{1-hydroxy-4-(methyloxy)-9-[(1-methylpropyl)oxy]-3-oxo-1,3-dihydro-2H- benzo[f]isoindol-2- yl}phenyl)acetate and Ethyl (4-{1 -hydroxy-9-(methyloxy)-4-[(1 - methylpropyl)oxy]-3-oxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl}phenyl)acetate
Figure imgf000059_0002
To a solution of ethyl (4-{4-(methyloxy)-9-[(1-methylpropyl)oxy]-1 ,3-dioxo-1 ,3- dihydro-2H-benzo[/]isoindol-2-yl}phenyl)acetate (0.419g, 0.909mmol) in ethanol (4ml) and tetrahydrofuran (8ml), was added sodium borohydride (0.104g, 2.74mmol) portion wise. The reaction was stirred for 1 hour then a further portion of sodium borohydride (0.208g, 5.47mmol) was added, stirring continued at room temperature for 1 hour. The mixture was quenched with aqueous saturated ammonium chloride solution and then evaporated. This was extracted x 2 with ethyl acetate, dried over magnesium sulphate and evaporated to give the crude product (0.414g, 0.894mmol). LC/MS: Rt=3.59, [MH]+464.
Description 60
{4-[4-(Butyloxy)-9-(ethyloxy)-1-oxo-1,3-dihydro-2H-benzo[f]isoindol-2- yljphenyl}acetic acid and {4-[9-(butyloxy)-4-(ethyloxy)-1-oxo-1,3-dihydro-2H- benzo[f]isoindol-2-yl]phenyl}acetic acid
Figure imgf000060_0001
To a solution of {4-[4-(butyloxy)-9-(ethyloxy)-3-hydroxy-1-oxo-1 ,3-dihydro-2/-/- benzo[f]isoindol-2-yl]phenyl}acetic acid and {4-[4-(butyloxy)-9-(ethyloxy)-1- hydroxy-3-oxo-1 ,3-dihydro-2H-benzo[/]isoindol-2-yl]phenyl}acetic acid (0.168g, 0.374mmol) in trifluoroacetic acid (1ml) cooled to 00C, was added triethylsilane (0.089ml, 0.561 mmol). Stirring continued at O0C for 10 minutes, and then the mixture was evaporated. The isomers were separated using supercritical fluid chromatography.
Example 16
{4-[4-(Butyloxy)-9-(ethyloxy)- 1-oxo- 1, 3-dihydro-2H-benzo[f]isoindol-2- yl]phenyl}acetic acid
(0.024g, 0.055mmol)
LC/MS: Rt=3.52, [MH]+434.
Figure imgf000061_0001
Example 17
{4-[9-(Butyloxy)-4-(ethyloxy)-1-oxo-1,3-dihydro-2H-benzo[f]isoindol-2- yl]phenyl}acetic acid
(0.042g, 0.097mmol)
LC/MS: Rt=3.54, [MH]+434
Figure imgf000061_0002
The following compounds were prepared in a similar manner to {4-[4-(butyloxy)- 9-(ethyloxy)-1 -oxo-1 ,3-dihydro-2/-/-benzo[/]isoindol-2-yl]phenyl}acetic acid and {4- [9-(butyloxy)-4-(ethyloxy)-1-oxo-1 ,3-dihydro-2/-/-benzo[/]isoindol-2- yl]phenyl}acetic acid using the appropriate starting materials.
Figure imgf000062_0001
Description 61
(4-{4-[(1-methylethyl)oxy]-9-[(2-methylpropyl)oxy]-1-oxo- 1, 3-dihydro-2H- benzo[f]isoindol-2-yl}phenyl)acetic acid - (4-{9-[(1-methylethyl)oxy]-4-[(2- methylpropyl)oxy]-1-oxo- 1, 3-dihydro-2H-benzo[f]isoindol-2-yl}phenyl)acetic acid
Figure imgf000063_0001
To a solution of the mixture of ethyl (4-{1-hydroxy-9-[(1-methylethyl)oxy]-4-[(2- methylpropyl)oxy]-3-oxo-1 ,3-dihydro-2H-benzo[f]isoindol-2-yl}phenyl)acetic acid and (4-{1-hydroxy-4-[(1-methylethyl)oxy]-9-[(2-methylpropyl)oxy]-3-oxo-1 ,3- dihydro-2/-/-benzo[/]isoindol-2-yl}phenyl)acetic acid (0.114g, 0.246mmol) in trifluoroacetic acid (1 ml) cooled to O0C, was added triethylsilane (0.059ml, 3.69mmol). Stirred at 00C until the red colour turned to a light yellow colour. This was evaporated. The crude reaction mixture of the two regioisomers were then taken on to the next reaction. LC/MS: Rt=3.65, [MH]+448.
The following compounds were prepared in a similar manner, (4-{4-[(1- methylethyl)oxy]-9-[(2-methylpropyl)oxy]-1-oxo-1 ,3-dihydro-2H-benzo[f]isoindol-2- yl}phenyl)acetic acid - (4-{9-[(1-methylethyl)oxy]-4-[(2-methylpropyl)oxy]-1-oxo- 1 ,3-dihydro-2H-benzo[f]isoindol-2-yl}phenyl)acetic acid using the appropriate starting materials.
Figure imgf000064_0001
Description 63
(+-)Ethyl (4-{4-(methyloxy)-9-[(1-methylpropyl)oxy]-1-oxo- 1, 3-dihydro-2H- benzo[f]isoindol-2- yl}phenyl)acetate
Figure imgf000064_0002
To a solution of ethyl (4-{1-hydroxy-4-(methyloxy)-9-[(1-methylpropyl)oxy]-3-oxo- 1 ,3-dihydro-2/-/-benzo[/]isoindol-2-yl}phenyl)acetate and ethyl (4-{1-hydroxy-9- (methyloxy)-4-[(1-methylpropyl)oxy]-3-oxo-1 ,3-dihydro-2/-/-benzo[/]isoindol-2- yl}phenyl)acetate (0.421 g, 0.909mmol) in trifluoroacetic acid (5ml) cooled to O0C1 was added triethylsilane (0.217ml, 1.36mmol). Stirring continued at 0°C for 15 minutes, and then the mixture was evaporated. The crude mixture was purified using chromatography on silica gel, eluting with ethyl acetate (0-30%) in hexane. The isomers were then separated using chiral supercritical fluid chromatography (only one regioisomer was isolated, but the two enantiomers were separated).
Ethyl (4-{4-(methyloxy)-9-[(1-methylpropyl)oxy]-1-oxo- 1, 3-dihydro-2H- benzo[f]isoindol-2-yl}phenyl)acetate - Enantiomer 1 (0.018g, 0.040mmol)
LC/MS: Rt=4.07, [MH]+448.
Figure imgf000065_0001
Ethyl (4-{4-(methyloxy)-9-[(1-methylpropyl)oxy]-1 -oxo-1, 3-dihydro-2H- benzo[f]isoindol-2-yl}phenyl)acetate - Enantiomer 2 (0.018g, 0.040mmol) LC/MS: Rt=4.07, [MH]+448.
Figure imgf000065_0002
Description 64
Ethyl (4-{9-[1-methylethoxy]-4-[(2-methylpropyl)oxy]-1 -oxo-1, 3-dihydro-2H- benzo[fjisoindol-2-yl}phenyl)acetate and ethyl (4-{4-[1 -methylethoxy]-9-[(2- methylpropyl)oxy]-1 -oxo-1, 3-dihydro-2H-benzo[f]isoindol-2-yl}phenyl)acetate
Figure imgf000066_0001
To a solution of (4-{9-[1-methylethoxy]-4-[(2-methylpropyl)oxy]-1-oxo-1 ,3-dihydro- 2/-/-benzo[/]isoindol-2-yl}phenyl)acetic acid and (4-{9-[1-methylethoxy]-4-[(2- methylpropyl)oxy]-1 -oxo-1 ,3-dihydro-2H-benzo[/]isoindol-2-yl}phenyl)acetic acid (0.098g, 0.22mmol) in ethanol (5ml) was added 3 drops of concentrated sulphuric acid. This was heated to 1000C for 30 minutes. The reaction was basified with 880 ammonia and then evaporated. The mixture was partitioned between x2 dichloromethane and water using a hydrophobic frit. The organic extracts were evaporated down. The isomers were separated using HPLC chromatography.
Ethyl (4-{4-[1-methylethoxy]-9-[(2-methylpropyl)oxy]-1 -oxo-1, 3-dihydro-2H- benzo[f]isoindol-2-yl}phenyl)acetate
(0.025g, 0.053mmol)
LC/MS: Rt=4.18 [MH]+476.
Figure imgf000066_0002
Ethyl (4-{9-[1-methylethoxy]-4-[(2-methylpropyl)oxy]-1 -oxo-1, 3-dihydro-2H- benzo[f]isoindol-2-yl}phenyl)acetate (0.039g, 0.082mmol) LC/MS: Rt=4.19, [MH]+476.
Figure imgf000067_0001
The following compound was prepared in a similar manner to ethyl (4-{9-[1- methylethoxy]-4-[(2-methylpropyl)oxy]-1 -oxo-1 , 3-dihydro-2H-benzo[/]isoindol-2- yl}phenyl)acetate and ethyl (4-{4-[1-methylethoxy]-9-[(2-methylpropyl)oxy]-1-oxo- 1 ,3-dihydro-2/-/-benzo[/]isoindol-2-yl}phenyl)acetate using the appropriate starting materials, except using methanol instead of ethanol
Figure imgf000067_0002
Example 20
(4-{4-(Methyloxy)-9-[(1-methylpropyl)oxy]-1 -oxo-1, 3-dihydro-2H-benzo[f]isoindol- 2-yl}phenyl)acetic acid
Figure imgf000068_0001
To a solution of ethyl (4-{4-(methyloxy)-9-[(1-methylpropyl)oxy]-1-oxo-1 ,3- dihydro-2/-/-benzo[/]isoindol-2-yl}phenyl)acetate (0.018g, 0.040mmol) in ethanol (2ml) was added 2N aqueous sodium hydroxide solution (2ml). This was heated to reflux for 1 hour. The ethanol was evaporated and the mixture acidified with 2N aqueous hydrochloric acid. The resulting solid was collected by filtration, washed with water and dried under vacuum to give the title compound (0.016g, 0.038mmol). LC/MS: Rt=3.51 , [MH]+420.
The following compounds were prepared in a similar manner to (4-{4- (methyloxy)-9-[(1 -methylpropyl)oxy]-1 -oxo-1 ,3-dihydro-2/-/-benzo[/]isoindol-2- yl}phenyl)acetic acid_using the appropriate starting materials. Example 24 was prepared using methanol as a solvent instead of ethanol.
Figure imgf000068_0002
Figure imgf000069_0001
Biological data
Studies were performed using HEK-293(T) cells expressing the recombinant human prostanoid EP4 receptor (HEK-EP4 cells). Cells were grown as a monolayer culture in DMEM-F12/F12 containing glutamax Il (Gibco) and supplemented with 10% foetal bovine serum and 0.4mg.ml-1 G418. HEK-EP4 cells were pre-treated 24hr and 30mins prior to the experiment with 10μM indomethacin and harvested using Versene containing 10μM indomethacin. The cells were resuspended in assay buffer (DMEM:F12, 10μM indomethacin and 200μM IBMX) at 1 x106 cells per ml and incubated for 20min at 37°C. Thereafter, 50μl of cells were added to 5OuI agonist (compound of Formula (I)) and incubated at 37°C for 4 minutes before stopping reactions with 100μl of 1% triton X-100. cAMP levels in the cell lysates were determined using a competition binding assay. In this assay the ability of cell lysates to inhibit 3H-cAMP (Amersham) binding to the binding subunit of protein kinase A was measured and cAMP levels were calculated from a standard curve. The data for each compound were expressed as a % of the response to a 1OnM maximal concentration of the standard agonist PGE2. For each compound the maximal response and concentration of compound causing 50% of its maximal response were calculated. Intrinsic activity is expressed relative to the maximal response to PGE2. Unless stated, reagents were purchased commercially from Sigma.
The examples of the present invention were tested in the above-mentioned assay and exhibited pEC50 values of 6.4 or higher and intrinsic activities of 30% or higher.

Claims

Claims
1. A compound selected from the group consisting of: {4-[1 ,3-Dioxo-4,9-bis(propyloxy)-1 ,3-dihydro-2H-benzo[f]isoindol-2-yl]-3- methylphenyljacetic acid;
[4-[4,9-Bis(ethyloxy)-1 ,3-dioxo-1 ,3-dihydro-2H-benzo[f]isoindol-2-yl]-3-
(methyloxy)phenyl]acetic acid;
[4-[4,9-Bis(ethyloxy)-1 ,3-dioxo-1 ,3-dihydro-2H-benzo[f]isoindol-2-yl]-3- (trifluoromethyl)phenyl]acetic acid;
{4-[4,9-Bis(ethyloxy)-1 ,3-dioxo-1 ,3-dihydro-2H-benzo[f]isoindol-2-yl]-3- methylphenyljacetic acid;
{4-[4,9-Bis(ethyloxy)-6-methyl-1 ,3-dioxo-1 ,3-dihydro-2H-benzo[/]isoindol-2- yl]phenyl}acetic acid; {3-Methyl-4-[1 -oxo-4, 9-bis(propyloxy)-1 ,3-dihydro-2H-benzo[f]isoindol-2- yl]phenyl}acetic acid;
(4-{4,9-Bis(1 -methylethoxy)-1 -oxo-1 ,3-dihydro-2H-benzo[f]isoindol-2-yl}-3- methylphenyl)acetic acid; μ-μ.θ-BisCethyloxyJ-i-oxo-I .S-dihydro^H-benzofflisoindol^-ylJ-S- (trifluoromethyl)phenyl]acetic acid;
(4-{4-(Ethyloxy)-1 ,3-dioxo-9-[(phenylmethyl)oxy]-1 ,3-dihydro-2H-benzo[f]isoindol-
2-yl}phenyl)acetic acid;
(4-{4-[1 -Methylethoxy]-9-[(2-methylpropyl)oxy]-1 ,3-dioxo-1 ,3-dihydro-2H- benzo[f]isoindol-2-yl}phenyl)acetic acid; (4-{4-[1-Methylethoxy]-9-[(1-methylpropyl)oxy]-1 ,3-dioxo-1 ,3-dihydro-2H- benzo[f]isoindol-2-yl}phenyl)acetic acid;
(4-{4-(Ethyloxy)-9-[(1-methylpropyl)oxy]-1 ,3-dioxo-1 ,3-dihydro-2H- benzo[f]isoindol-2-yl}phenyl)acetic acid;
(4-{4-(Ethyloxy)-9-[(2-methylpropyl)oxy]-1 ,3-dioxo-1 ,3-dihydro-2H- benzo[f]isoindol-2-yl}phenyl)acetic acid;
{4-[4-(Butyloxy)-9-(ethyloxy)-1 ,3-dioxo-1 ,3-dihydro-2H-benzo[f]isoindol-2- yl]phenyl}acetic acid; (4-{4-(Methyloxy)-9-[(1 -methylpropyl)oxy]-1 ,3-dioxo-1 ,3-dihydro-2H- benzo[f]isoindol-2-y!}phenyl)acetic acid;
{4-[4-(Butyloxy)-9-(ethyloxy)-1-oxo-1 ,3-dihydro-2H-benzo[f]isoindol-2- yl]phenyl}acetic acid; {4-[9-(Butyloxy)-4-(ethyloxy)-1 -oxo-1 ,3-dihydro-2H-benzo[f]isoindol-2- yl]phenyl}acetic acid;
(4-{4-(Ethyloxy)-9-[(1-methylpropyl)oxy]-1 -oxo-1 , 3-dihydro-2H-benzo[f]isoindol-2- yl}phenyl)acetic acid;
(4-{9-(Ethyloxy)-4-[(2-methylpropyl)oxy]-1-oxo-1 ,3-dihydro-2H-benzo[f]isoindol-2- yl}phenyl)acetic acid;
-f?-(4-{4-(Methyloxy)-9-[(1 -methylpropyl)oxy]-1 -oxo-1 ,3-dihydro-2H- benzo[f]isoindol-2-yl}phenyl)acetic acid;
-S-(4-{4-(Methyloxy)-9-[(1 -methylpropyl)oxy]-1 -oxo-1 , 3-dihydro-2H- benzo[f]isoindol-2-yl}phenyl)acetic acid; (4-{4-[1-Methylethoxy]-9-[(2-methylpropyl)oxy]-1 -oxo-1 , 3-dihydro-2H- benzo[f]isoindol-2-yl}phenyl)acetic acid;
(4-{9-[1 -Methylethoxy]-4-[(2-methylpropyl)oxy]-1 -oxo-1 ,3-dihydro-2H- benzo[f]isoindol-2-yl}phenyl)acetic acid;
(4-{9-(Butyloxy)-4-[1-methylethoxy]-1-oxo-1 ,3-dihydro-2H-benzo[f]isoindol-2- yl}phenyl)acetic acid; and a pharmaceutically acceptable derivative thereof.
2. A compound according to claim 1 , for use in human or veterinary medicine.
3. A compound according to claim 1 , for use in the treatment of a condition which is mediated by the action, or loss of action, of PGE2 at EP4 receptors.
4. A method of treating a human or animal subject suffering from a condition which is mediated by the action, or by loss of action, of PGE2 at EP4 receptors which comprises administering to said subject an effective amount of a compound according to claim 1.
5. Use of a compound according to claim 1 , for the manufacture of a medicament for the treatment of a condition which is mediated by the action of PGE2 at EP4 receptors.
6. A pharmaceutical composition comprising a compound according to claim 1 and one or more acceptable carriers or diluents therefor.
7. A pharmaceutical composition according to claim 6, comprising one or more additional therapeutic agents.
PCT/EP2007/062497 2006-11-21 2007-11-19 Benzoisoindole derivatives and their use as ep4 receptor agonists WO2008061955A1 (en)

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